Arylethynyl Derivatives

ABSTRACT

The present invention relates to ethynyl compounds of formula I 
     
       
         
         
             
             
         
       
     
     wherein
     R1, R2, R2′, R3, R3′, R4, R4′, U, V, W, Y, m, and n are as defined herein and to a pharmaceutically acceptable acid addition salts, to a racemic mixtures, or to its corresponding enantiomers and/or optical isomers and/or stereoisomers thereof. Compounds of formula I are allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of U.S. patent application Ser. No. 13/779,782, filed Feb. 28, 2013, which is a Divisional of U.S. patent application Ser. No. 13/066,044, filed Apr. 5, 2011, now U.S. Pat. No. 8,420,661, which claims the benefit of European Patent Application No. 10159754.0, filed Apr. 13, 2010. Each of these applications is hereby incorporated by reference herein in its entirety.

BACKGROUND OF THE INVENTION

In the central nervous system (CNS) the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor.

Glutamate is the major excitatory neurotransmitter in the brain and plays a unique role in a variety of central nervous system (CNS) functions. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group, namely the ionotropic receptors, forms ligand-controlled ion channels. The metabotropic glutamate receptors (mGluR) belong to the second main group and, furthermore, belong to the family of G-protein coupled receptors.

At present, eight different members of these mGluR are known and of these some even have sub-types. According to their sequence homology, signal transduction mechanisms and agonist selectivity, these eight receptors can be sub-divided into three sub-groups:

mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.

Ligands of metabotropic glutamate receptors belonging to the first group can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, epilepsy, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits, as well as chronic and acute pain.

Other treatable indications in this connection are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are ischemia, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depressions.

Disorders mediated full or in part by mGluR5 are for example acute, traumatic and chronic degenerative processes of the nervous system, such as Alzheimer's disease, senile dementia, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis, psychiatric diseases such as schizophrenia and anxiety, depression, pain and drug dependency (Expert Opin. Ther. Patents (2002), 12, (12)).

A new avenue for developing selective modulators is to identify compounds which act through allosteric mechanism, modulating the receptor by binding to a site different from the highly conserved orthosteric binding site. Allosteric modulators of mGluR5 have emerged recently as novel pharmaceutical entities offering this attractive alternative. Allosteric modulators have been described, for example in WO2008/151184, WO2006/048771, WO2006/129199 and WO2005/044797 and in Molecular Pharmacology, 40, 333-336, 1991; The Journal of Pharmacology and Experimental Therapeutics, Vol 313, No. 1, 199-206, 2005;

In recent years there have been significant advantages in understanding the pathophysiology of several disorders of brain development, suggesting that protein synthesis at synapses is triggered by activation of group I metabotropic glutamate receptors. Such disorders include fragile X syndrome, autism, idiopatic autism, tuberous sclerosis complex disorder, neurofibromatosis type 1 or Rett syndrome (Annu. Rev. Med., 2011, 62, 31.1-31.19 and Neuroscience 156, 2008, 203-215).

Described in the prior art are positive allosteric modulators. They are compounds that do not directly activate receptors by themselves, but markedly potentiate agonist-stimulated responses, increase potency and maximum of efficacy. The binding of these compounds increases the affinity of a glutamate-site agonist at its extracellular N-terminal binding site. Allosteric modulation is thus an attractive mechanism for enhancing appropriate physiological receptor activation. There is a scarcity of selective allosteric modulators for the mGluR5 receptor. Conventional mGluR5 receptor modulators typically lack satisfactory aqueous solubility and exhibit poor oral bioavailability.

Therefore, there remains a need for compounds that overcome these deficiencies and that effectively provide selective allosteric modulators for the mGluR5 receptor.

SUMMARY OF THE INVENTION

The present invention provides ethynyl compounds of formula I

wherein

-   U is ═N— or ═C(R⁵)—; -   V is —CH═ or —N═; -   W is ═CH— or ═N—;     -   with the proviso that only one of U, V or W is nitrogen, -   R⁵ is hydrogen, methyl or halogen; -   Y is —N(R⁶)—, —O—, —C(R^(7′))(R⁷)—, —CH₂O— or —CH₂S(O)₂—;     -   wherein R⁶ is hydrogen or lower alkyl and R⁷ and R^(7′) are each         independently hydrogen, hydroxy, lower alkyl or lower alkoxy; -   R¹ is phenyl or heteroaryl, each of which is optionally substituted     by one or two substituents, selected from halogen, lower alkyl and     lower alkoxy; -   R² and R^(2′) are each independently hydrogen, lower alkyl, hydroxy,     lower alkoxy, C₃-C₆-cycloalkyl, or CH₂-lower alkoxy, or together     with the carbon atom to which they are attached form a     C₃-C₆-cycloalkyl group or a ring containing —CH₂OCH₂—; -   m is 0, 1 or 2;     -   when m is 1, -   R³ and R^(3′) are each independently hydrogen, lower alkyl, or     CH₂-lower alkoxy or together with the carbon atom to which they are     attached form a C₃-C₆-cycloalkyl group;     -   or R³ and R² together with the carbon atom to which they are         attached form a C₃₋₆-cycloalkyl group or a ring containing         —(CH₂)₂OCH₂—; -   n is 0 or 1; and     -   when n is 1, -   R⁴ and R^(4′) are each independently hydrogen, lower alkyl, or     CH₂-lower alkoxy or together with the carbon atom to which they are     attached form a C₃-C₆-cycloalkyl; or     -   R⁴ and R² together with the carbon atom to which they are         attached form a C₃₋₆-cycloalkyl group;         or when n is 0 and Y is —N(R⁶)—, then R⁶ and R² together with         the carbon atom and the nitrogen atom to which they are attached         form a C₃₋₆-cycloalkyl group;         or when n and m are 0, then R² and R⁷ together with the carbon         atoms to which they are attached form a C₃₋₆-cycloalkyl group;         or a pharmaceutically acceptable acid addition salt, a racemic         mixture, an enantiomer, an isomer, and/or a stereoisomer         thereof.

The present invention provides compounds of formula I per se, their pharmaceutically acceptable salts, and mixtures of enantiomers or diastereomers or their enantiomerically or diastereomerically pure forms. The invention also provides pharmaceutical compositions containing a therapeutically effective amount of such compounds and process for the production of such compounds and compositions.

Compounds of formula I are allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5). They can be used in the treatment or prevention of disorders relating to allosteric modulators for the mGluR5 receptor. For example, the compounds can be used for the treatment or prevention of disorders, relating to allosteric modulators for the mGluR5 receptor, such as schizophrenia, cognition, fragile X syndrome or autism, and to pharmaceutical compositions containing the compounds of formula I. The most preferred indications are schizophrenia and cognition.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.

As used herein, the term “lower alkyl” denotes a saturated, i.e. aliphatic hydrocarbon group including a straight or branched carbon chain with 1-4 carbon atoms. Examples for “alkyl” are methyl, ethyl, n-propyl, and isopropyl.

The term “lower alkoxy” denotes a group —O—R′ wherein R′ is lower alkyl as defined above.

The term “halogen” denotes the chlorine, fluorine, bromine, or iodine.

The term “ethynyl” denotes the group —C≡C—.

The term “cycloalkyl” denotes a saturated carbon ring, containing from 3 to 6 carbon ring atoms, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term “heteroaryl” denotes a 5 or 6-membered aromatic ring, containing at least one N, O or S-heteroatom, for example pyridinyl, pyrimidinyl, pyrazolyl, pyridazinyl, imidazolyl, triazolyl, thienyl or pyrazinyl.

“Pharmaceutically acceptable,” such as pharmaceutically acceptable carrier, excipient, etc., denotes pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.

The term “pharmaceutically acceptable salt” or “pharmaceutically acceptable acid addition salt” embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.

“Therapeutically effective amount” denotes an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.

One embodiment of the invention provides compounds of formula I-1

wherein

-   U is ═N— or ═C(R⁵)—; -   V is —CH═ or —N═; -   W is ═CH— or ═N—;     -   with the proviso that only one of U, V or W is nitrogen. -   R⁵ is hydrogen, methyl or halogen; -   R¹ is phenyl or heteroaryl, each of which is optionally substituted     by one or two substituents, selected from halogen, lower alkyl and     lower alkoxy; -   R² and R^(2′) are each independently hydrogen, lower alkyl, hydroxy,     lower alkoxy, C₃-C₆-cycloalkyl, or CH₂-lower alkoxy, or together     with the carbon atom to which they are attached form a     C₃-C₆-cycloalkyl group or a ring containing —CH₂OCH₂—; and -   R³ and R^(3′) are each independently hydrogen, lower alkyl, or     CH₂-lower alkoxy or together with the carbon atom to which they are     attached form a C₃-C₆-cycloalkyl group;     -   or R³ and R² together with the carbon atom to which they are         attached form a C₃₋₆-cycloalkyl group or a ring containing         —(CH₂)₂OCH₂—;         or a pharmaceutically acceptable acid addition salt, a racemic         mixture, an enantiomer, an optical isomer, and/or stereoisomer         thereof.

Examples of compounds of formula I-A1 are the following:

-   3-(3-fluoro-5-phenylethynyl-pyridin-2-yl)-5,5-dimethyl-oxazolidin-2-one; -   (5RS)-5-methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one; -   (5R or     5S)-5-methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one; -   (5S or     5R)-5-methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one; -   5,5-dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one; -   3-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one; -   5,5-dimethyl-3-(5-pyridin-3-ylethynyl-pyridin-2-yl)-oxazolidin-2-one; -   (5RS)-5-tert-butyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one; -   6-(5-phenylethynyl-pyridin-2-yl)-4-oxa-6-aza-spiro[2.4]heptan-5-one; -   7-(5-phenylethynyl-pyridin-2-yl)-5-oxa-7-aza-spiro[3.4]octan-6-one; -   3-(5-phenylethynyl-pyridin-2-yl)-1-oxa-3-aza-spiro[4.4]nonan-2-one; -   3-(5-phenylethynyl-pyridin-2-yl)-1-oxa-3-aza-spiro[4.5]decan-2-one; -   (5RS)-5-tert-butyl-5-methyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one; -   (3aRS,6aSR)-3-(5-phenylethynyl-pyridin-2-yl)-hexahydro-cyclopentaoxazol-2-one; -   (3aRS,6aSR)-3-(5-pyridin-3-ylethynyl-pyridin-2-yl)-hexahydro-cyclopentaoxazol-2-one; -   (3aRS,6aSR)-3-[5-(5-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-hexahydro-cyclopentaoxazol-2-one; -   (RS)-4,5,5-trimethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one; -   4,4,5,5-tetramethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one; -   3-[5-(5-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one; -   5,5-dimethyl-3-(5-pyrimidin-5-ylethynyl-pyridin-2-yl)-oxazolidin-2-one; -   5,5-dimethyl-3-[5-(1-methyl-1H-pyrazol-4-ylethynyl)-pyridin-2-yl]-oxazolidin-2-one; -   3-[5-(4-fluoro-phenylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one; -   3-[5-(3,4-difluoro-phenylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one; -   3-[5-(2,5-difluoro-phenylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one; -   3-[5-(6-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one; -   6-(5-pyridin-3-ylethynyl-pyridin-2-yl)-4-oxa-6-aza-spiro[2.4]heptan-5-one; -   (6SR,7RS)-3-(5-phenylethynyl-pyridin-2-yl)-hexahydro-benzooxazol-2-one; -   (3aSR,7aRS)-(3     aRS,7RS)-1-(5-phenylethynyl-pyridin-2-yl)-hexahydro-pyrano[4,3-d]oxazol-2-one;     and -   5,5-dimethyl-3-(6-(phenylethynyl)pyridazin-3-yl)oxazolidin-2-one.

A further embodiment of the invention provides compounds of formula I-B1

wherein

-   U is ═N— or ═C(R⁵)—; -   V is —CH═ or —N═; -   W is ═CH— or ═N—;     -   with the proviso that only one of U, V or W is nitrogen. -   R⁵ is hydrogen, methyl or halogen; -   R¹ is phenyl or heteroaryl, each of which is optionally substituted     by one or two substituents, selected from halogen, lower alkyl and     lower alkoxy; -   R² and R^(2′) are each independently hydrogen, lower alkyl, hydroxy,     lower alkoxy, C₃-C₆-cycloalkyl, or CH₂-lower alkoxy, or together     with the carbon atom to which they are attached form a     C₃-C₆-cycloalkyl group or a ring containing     -   —CH₂OCH₂—; -   R³ and R^(3′) are each independently hydrogen, lower alkyl, or     CH₂-lower alkoxy or together with the carbon atom to which they are     attached form a C₃-C₆-cycloalkyl group; or R³ and R² together with     the carbon atom to which they are attached form a C₃₋₆-cycloalkyl     group or a ring containing —(CH₂)₂OCH₂—; and -   R⁷ and R^(7′) are each independently hydrogen, hydroxy, lower alkyl     or lower alkoxy;     or a pharmaceutically acceptable acid addition salt, a racemic     mixture, an enantiomer, an optical isomer, and/or stereoisomer     thereof.

Specific examples of compounds of formula I-B1 are the following:

-   4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one; -   (3RS)-3-hydroxy-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one; -   1-(3-fluoro-5-phenylethynyl-pyridin-2-yl)-4,4-dimethyl-pyrrolidin-2-one; -   1-[5-(5-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-one; -   4,4-dimethyl-1-(5-pyridin-3-ylethynyl-pyridin-2-yl)-pyrrolidin-2-one; -   1-[5-(5-chloro-pyridin-3-ylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-one; -   1-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-one; -   4,4-dimethyl-1-(3-methyl-5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one; -   2-(5-phenylethynyl-pyridin-2-yl)-2-aza-spiro[4.4]nonan-3-one; -   (RS)-3-methoxy-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one; -   (5R or     5S)-5-methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one; -   (5S or     5R)-5-methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one; -   (RS)-1-[5-(5-chloro-pyridin-3-ylethynyl)-pyridin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one; -   (RS)-3-methoxy-4,4-dimethyl-1-(5-m-tolylethynyl-pyridin-2-yl)-pyrrolidin-2-one; -   (RS)-1-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one; -   (RS)-1-[5-(4-fluoro-phenylethynyl)-pyridin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one; -   6-(5-phenylethynyl-pyridin-2-yl)-2-oxa-6-aza-spiro[3.4]octan-7-one; -   4,4-dimethyl-5′-phenylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one; -   5′-(3-fluoro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one; -   5′-(3-chloro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one; -   5′-(5-chloro-pyridin-3-ylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one; -   5′-(4-fluoro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one; -   5′-(2,5-difluoro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one; -   4,4-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one; -   2-(5-phenylethynyl-pyrimidin-2-yl)-2-aza-spiro[4.4]nonan-3-one; -   1-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2-one; -   1-[5-(3-chloro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2-one; -   1-[5-(4-fluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2-one; -   1-[5-(2,5-difluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2-one; -   (RS)-3-methoxy-4,4-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one; -   (5R or     5S)-5-methoxymethyl-3-(5-phenylethynyl-pyrimidin-2-yl)-oxazolidin-2-one; -   (5S or     5R)-5-methoxymethyl-3-(5-phenylethynyl-pyrimidin-2-yl)-oxazolidin-2-one; -   (RS)-1-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one; -   (R or     S)-1-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one; -   (S or     R)-1-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one; -   (R or     S)-1-[5-(2,5-difluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one; -   4,4-dimethyl-1-(6-(phenylethynyl)pyridazin-3-yl)pyrrolidin-2-one;     and -   4,4-dimethyl-1-(5-(pyridin-3-ylethynyl)pyrazin-2-yl)pyrrolidin-2-one.

A further embodiment of the invention provides compounds of formula I-C1

wherein

-   U is ═N— or ═C(R⁵)—; -   V is —CH═ or —N═; -   W is ═CH— or ═N—;     -   with the proviso that only one of U, V or W is nitrogen. -   R⁵ is hydrogen, methyl or halogen; -   R⁶ is hydrogen or lower alkyl; -   R¹ is phenyl or heteroaryl, each of which is optionally substituted     by one or two substituents, selected from halogen, lower alkyl and     lower alkoxy; -   R² and R^(2′) are each independently hydrogen, lower alkyl, hydroxy,     lower alkoxy, C₃-C₆-cycloalkyl, or CH₂-lower alkoxy, or together     with the carbon atom to which they are attached form a     C₃-C₆-cycloalkyl group or a ring containing —CH₂OCH₂—; and -   R³ and R^(3′) are each independently hydrogen, lower alkyl, or     CH₂-lower alkoxy or together with the carbon atom to which they are     attached form a C₃-C₆-cycloalkyl group;     -   or R³ and R² together with the carbon atom to which they are         attached form a C₃₋₆-cycloalkyl group or a ring containing         —(CH₂)₂OCH₂—; -   Or R⁶ and R² together with the carbon atom and the nitrogen atom to     which they are attached form a C₃₋₆-cycloalkyl;     or a pharmaceutically acceptable acid addition salt, a racemic     mixture, an enantiomer, an optical isomer and/or stereoisomer     thereof.

Examples of compounds of formula I-C1 are the following:

-   4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one; -   3,4,4-trimethyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one; -   3-ethyl-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one; -   3-isopropyl-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one; -   1-methyl-3-(5-phenylethynyl-pyridin-2-yl)-1,3-diaza-spiro[4.4]nonan-2-one; -   (RS)-4-cyclopentyl-3-methyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one; -   3,4,4-trimethyl-1-(5-pyridin-3-ylethynyl-pyridin-2-yl)-imidazolidin-2-one; -   1-[5-(5-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one; -   3,4,4-trimethyl-1-[5-(1-methyl-1H-pyrazol-4-ylethynyl)-pyridin-2-yl]-imidazolidin-2-one; -   1-[5-(5-chloro-pyridin-3-ylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one; -   3,4,4-trimethyl-1-(5-pyridazin-4-ylethynyl-pyridin-2-yl)-imidazolidin-2-one; -   1-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one; -   1-[5-(3-chloro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one; -   3,4,4-trimethyl-1-(5-pyrimidin-5-ylethynyl-pyridin-2-yl)-imidazolidin-2-one; -   3,4,4-trimethyl-1-(5-m-tolylethynyl-pyridin-2-yl)-imidazolidin-2-one; -   1-[5-(4-fluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one; -   (RS)-2-(5-phenylethynyl-pyridin-2-yl)-hexahydro-imidazo[1,5-a]pyridin-3-one; -   (RS)-2-(5-pyridin-3-ylethynyl-pyridin-2-yl)-hexahydro-imidazo[1,5-a]pyridin-3-one; -   (RS)-2-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-hexahydro-imidazo[1,5-a]pyridin-3-one; -   (RS)-4-cyclopropyl-3-methyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one; -   (3aSR,7aRS)-(3     aRS,7RS)-1-methyl-3-(5-phenylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one; -   (3aSR,7aRS)-(3     aRS,7RS)-1-methyl-3-(5-pyridin-3-ylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one; -   (3aSR,7aRS)-(3     aRS,7RS)-1-[5-(5-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-3-methyl-octahydro-benzoimidazol-2-one; -   4-methyl-6-(5-phenylethynyl-pyridin-2-yl)-4,6-diaza-spiro[2.4]heptan-5-one; -   (3aSR,7aRS)-(3     aRS,7RS)-1-ethyl-3-(5-phenylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one; -   (3aSR,7aRS)-(3     aRS,7RS)-1-ethyl-3-(5-pyridin-3-ylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one; -   (3aSR,7aRS)-(3     aRS,7RS)-1-isopropyl-3-(5-phenylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one; -   (3aRS, 6aSR)-1-methyl-3-(5-(phenylethynyl)     pyridin-2-yl)hexahydrocyclopenta[d]imidazol-2(1H)-one; -   (RS)-4-tert-butyl-3-methyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one; -   1-[5-(3-fluoro-phenylethynyl)-3-methyl-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one; -   (3aSR,6aRS)-1-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-3-methyl-hexahydro-cyclopenta-imidazol-2-one; -   1-[3-fluoro-5-(4-fluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one; -   1-[3-fluoro-5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one; -   6-[5-(4-fluoro-phenylethynyl)-pyridin-2-yl]-4-methyl-4,6-diaza-spiro[2.4]heptan-5-one; -   6-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-4-methyl-4,6-diaza-spiro[2.4]heptan-5-one; -   3,4,4-trimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-imidazolidin-2-one; -   1-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one; -   1-[5-(2,5-difluoro-phenylethynyl)-pyrimidin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one; -   1-[5-(4-fluoro-phenylethynyl)-pyrimidin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one; -   1-[5-(3,4-di-fluoro-phenylethynyl)-pyrimidin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one; -   3-isopropyl-4,4-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-imidazolidin-2-one; -   1-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-3-isopropyl-4,4-dimethyl-imidazolidin-2-one; -   1-[5-(4-fluoro-phenylethynyl)-pyrimidin-2-yl]-3-isopropyl-4,4-dimethyl-imidazolidin-2-one; -   1-[5-(4-fluoro-phenylethynyl)-pyrimidin-2-yl]-3-ethyl-4,4-dimethyl-imidazolidin-2-one; -   1-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-3-ethyl-4,4-dimethyl-imidazolidin-2-one; -   4-methyl-6-(5-phenylethynyl-pyrimidin-2-yl)-4,6-diaza-spiro[2.4]heptan-5-one; -   3,4,4-trimethyl-1-(6-(m-tolylethynyl)pyridazin-3-yl)imidazolidin-2-one; -   1-(6-((3-chlorophenyl)ethynyl)pyridazin-3-yl)-3,4,4-trimethylimidazolidin-2-one; -   3,4,4-trimethyl-1-(5-(phenylethynyl)pyrazin-2-yl)imidazolidin-2-one; -   3,4,4-trimethyl-1-(5-(pyridin-3-ylethynyl)pyrazin-2-yl)imidazolidin-2-one; -   1-(5-((3-fluorophenyl)ethynyl)pyrazin-2-yl)-3,4,4-trimethylimidazolidin-2-one; -   1-(5-((4-fluorophenyl)ethynyl)pyrazin-2-yl)-3,4,4-trimethylimidazolidin-2-one; -   (3aRS,6aSR)-1-methyl-3-(6-phenylethynyl-pyridazin-3-yl)-hexahydro-cyclopentaimidazol-2-one;     and -   (3aSR,6aRS)-1-[6-(3-fluoro-phenylethynyl)-pyridazin-3-yl]-3-methyl-hexahydro-cyclopentaimidazol-2-one.

A further embodiment of the invention provides compounds of formula I-D1

wherein

-   U is ═N— or ═C(R⁵)—; -   V is —CH═ or —N═; -   W is ═CH— or ═N—;     -   with the proviso that only one of U, V or W is nitrogen. -   R⁵ is hydrogen, methyl or halogen; -   R¹ is phenyl or heteroaryl, each of which is optionally substituted     by one or two substituents, selected from halogen, lower alkyl and     lower alkoxy; -   R² and R^(2′) are each independently hydrogen, lower alkyl, hydroxy,     lower alkoxy, C₃-C₆-cycloalkyl, or CH₂-lower alkoxy, or together     with the carbon atom to which they are attached form a     C₃-C₆-cycloalkyl group or a ring containing —CH₂OCH₂—; -   R³ and R^(3′) are each independently hydrogen, lower alkyl, or     CH₂-lower alkoxy or together with the carbon atom to which they are     attached form a C₃-C₆-cycloalkyl group; or R³ and R² together with     the carbon atom to which they are attached form a C₃₋₆-cycloalkyl     group or a ring containing —(CH₂)₂OCH₂—; and -   R⁴ and R^(4′) are each independently hydrogen, lower alkyl, or     CH₂-lower alkoxy or together with the carbon atom to which they are     attached from a C₃-C₆-cycloalkyl; -   R⁴ and R^(4′) together with the carbon atom to which they are     attached form a C₃₋₆-cycloalkyl;     or a pharmaceutically acceptable acid addition salt, a racemic     mixture, an enantiomer, an optical isomer and/or stereoisomer     thereof.

Examples of compounds of formula I-D1 are the following:

-   5,5-dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one; -   6,6-dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one; -   6,6-dimethyl-3-(5-pyridin-3-ylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one; -   3-[5-(5-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one; -   3-[5-(5-chloro-pyridin-3-ylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one; -   3-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one; -   3-[5-(3-chloro-phenylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one; -   6,6-dimethyl-3-(5-m-tolylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one; -   3-[5-(4-fluoro-phenylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one; -   3-[5-(3,4-difluoro-phenylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one; -   3-[5-(2,5-difluoro-phenylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one; -   7,7-dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazepan-2-one; -   (RS)-5-hydroxy-6,6-dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one; -   (4aRS,7aSR)-3-(5-phenylethynyl-pyridin-2-yl)-hexahydro-cyclopenta[e][1,3]oxazin-2-one; -   (4aRS,7aRS)-3-(5-phenylethynyl-pyridin-2-yl)-hexahydro-cyclopenta[e][1,3]oxazin-2-one; -   (RS)-5,6,6-trimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one; -   (RS)-6-methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one; -   (RS)-5-methoxy-6,6-dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one; -   (RS)-5,6,6-trimethyl-3-(5-phenylethynyl-pyrimidin-2-yl)-[1,3]oxazinan-2-one; -   (RS)-3-[5-(2,5-difluoro-phenylethynyl)-pyrimidin-2-yl]-5,6,6-trimethyl-[1,3]oxazinan-2-one; -   (RS)-3-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-5,6,6-trimethyl-[1,3]oxazinan-2-one; -   (RS)-3-[5-(4-fluoro-phenylethynyl)-pyrimidin-2-yl]-5,6,6-trimethyl-[1,3]oxazinan-2-one; -   6,6-dimethyl-3-(6-(phenylethynyl)pyridazin-3-yl)-1,3-oxazinan-2-one; -   6,6-dimethyl-3-(5-(phenylethynyl)pyrazin-2-yl)-1,3-oxazinan-2-one;     and -   (RS)-3-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-5-methoxy-6,6-dimethyl-[1,3]oxazinan-2-one.

A further embodiment of the invention provides compounds of formula I-E1

wherein

-   U is ═N— or ═C(R⁵)—; -   V is —CH═ or —N═; -   W is ═CH— or ═N—;     -   with the proviso that only one of U, V or W is nitrogen. -   R⁵ is hydrogen, methyl or halogen; -   R⁷ and R^(7′) are each independently hydrogen, hydroxy, lower alkyl     or lower alkoxy; -   R¹ is phenyl or heteroaryl, each of which is optionally substituted     by one or two substituents, selected from halogen, lower alkyl and     lower alkoxy; -   R² and R^(2′) are each independently hydrogen, lower alkyl, hydroxy,     lower alkoxy, C₃-C₆-cycloalkyl, or CH₂-lower alkoxy, or together     with the carbon atom to which they are attached form a     C₃-C₆-cycloalkyl group or a ring containing     -   —CH₂OCH₂—; -   R³ and R^(3′) are each independently hydrogen, lower alkyl, or     CH₂-lower alkoxy or together with the carbon atom to which they are     attached form a C₃-C₆-cycloalkyl group;     -   or R³ and R² together with the carbon atom to which they are         attached form a C₃₋₆-cycloalkyl group or a ring containing         —(CH₂)₂OCH₂—; and -   R⁴ and R^(4′) are each independently hydrogen, lower alkyl, or     CH₂-lower alkoxy or together with the carbon atom to which they are     attached form a C₃-C₆-cycloalkyl group; -   R⁴ and R² together with the carbon atom to which they are attached     form a C₃₋₆-cycloalkyl group;     or a pharmaceutically acceptable acid addition salt, a racemic     mixture, an enantiomer, an optical isomer and/or stereoisomer     thereof.

Specific examples of compounds of formula I-E1 are the following:

-   5,5-dimethyl-5′-phenylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one; -   5′-(3-fluoro-phenylethynyl)-5,5-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one; -   5,5-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-piperidin-2-one; -   4,4-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-piperidin-2-one; -   1-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-piperidin-2-one; -   1-[5-(2,5-difluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-piperidin-2-one; -   4,4-dimethyl-1-(6-(phenylethynyl)pyridazin-3-yl)piperidin-2-one; -   1-(5-((3-fluorophenyl)ethynyl)pyrazin-2-yl)-4,4-dimethylpiperidin-2-one; -   4,4-dimethyl-1-(5-(pyridin-3-ylethynyl)pyrazin-2-yl)piperidin-2-one;     and -   4,4-dimethyl-1-(5-(phenylethynyl)pyrazin-2-yl)piperidin-2-one.

A further embodiment of the invention provides compounds of formula I-F1

wherein

-   U is ═N— or ═C(R⁵)—; -   V is —CH═ or —N═; -   W is ═CH— or ═N—;     -   with the proviso that only one of U, V or W is nitrogen. -   R⁵ is hydrogen, methyl or halogen; -   R⁶ is hydrogen or lower alkyl; -   R¹ is phenyl or heteroaryl, each of which is optionally substituted     by one or two substituents, selected from halogen, lower alkyl and     lower alkoxy; -   R² and R^(2′) are each independently hydrogen, lower alkyl, hydroxy,     lower alkoxy, C₃-C₆-cycloalkyl, or CH₂-lower alkoxy, or together     with the carbon atom to which they are attached form a     C₃-C₆-cycloalkyl group or a ring containing     -   —CH₂OCH₂—; -   R³ and R^(3′) are each independently hydrogen, lower alkyl, or     CH₂-lower alkoxy or together with the carbon atom to which they are     attached form a C₃-C₆-cycloalkyl group;     -   or R³ and R² together with the carbon atom to which they are         attached form a C₃₋₆-cycloalkyl group or a ring containing         —(CH₂)₂OCH₂—; and -   R⁴ and R^(4′) are each independently hydrogen, lower alkyl, or     CH₂-lower alkoxy or together with the carbon atom to which they are     attached form a C₃-C₆-cycloalkyl group; or -   R⁴ and R² together with the carbon atom to which they are attached     form a C₃₋₆-cycloalkyl;     or a pharmaceutically acceptable acid addition salt, a racemic     mixture, an enantiomer, an optical isomer and/or stereoisomer     thereof.

Examples of compounds of formula I-F1 are the following:

-   5,5-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-tetrahydro-pyrimidin-2-one; -   1,5,5-trimethyl-3-(5-phenylethynyl-pyridin-2-yl)-tetrahydro-pyrimidin-2-one; -   3,4,4-trimethyl-1-(5-phenylethynyl-pyridin-2-yl)-tetrahydro-pyrimidin-2-one; -   1-[5-(2,5-difluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-tetrahydro-pyrimidin-2-one; -   1-[5-(4-fluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-tetrahydro-pyrimidin-2-one; -   3,4,4-trimethyl-5′-phenylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one; -   5′-(3-fluoro-phenylethynyl)-3,4,4-trimethyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one; -   5′-(2,5-difluoro-phenylethynyl)-3,4,4-trimethyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one; -   4,4-dimethyl-1-(5-(phenylethynyl)pyrazin-2-yl)tetrahydropyrimidin-2(1H)-one; -   3,4,4-trimethyl-1-(5-(phenylethynyl)pyrazin-2-yl)tetrahydropyrimidin-2(1H)-one; -   1-(5-((3-fluorophenyl)ethynyl)pyrazin-2-yl)-4,4-dimethyltetrahydropyrimidin-2(1H)-one;     and -   1-(5-((3-fluorophenyl)ethynyl)pyrazin-2-yl)-3,4,4-trimethyltetrahydropyrimidin-2(1H)-one.

A further embodiment of the invention provides compounds of formula I-G1

wherein

-   U is ═N— or ═C(R⁵)—; -   V is —CH═ or —N═; -   W is ═CH— or ═N—;     -   with the proviso that only one of U, V or W is nitrogen. -   R⁵ is hydrogen, methyl or halogen; -   Y is —N(R⁶)—, —O—, —C(R^(7′))(R⁷)—, —CH₂O— or —CH₂S(O)₂—;     -   wherein R⁶ is hydrogen or lower alkyl and R⁷ and R^(7′) are each         independently hydrogen, hydroxy, lower alkyl and lower alkoxy; -   R¹ is phenyl or heteroaryl, each of which is optionally substituted     by one or two substituents, selected from halogen, lower alkyl and     lower alkoxy; and -   R² and R^(2′) are each independently hydrogen, lower alkyl, hydroxy,     lower alkoxy, C₃-C₆-cycloalkyl, or CH₂-lower alkoxy, or together     with the carbon atom to which they are attached form a     C₃-C₆-cycloalkyl group or a ring containing     -   —CH₂OCH₂—; -   or R⁶ and R² together with the carbon atom and the nitrogen atom to     which they are attached form a C₃₋₆-cycloalkyl group; -   or R² and R⁷ together with the carbon atoms to which they are     attached form a C₃₋₆-cycloalkylgroup;     or a pharmaceutically acceptable acid addition salt, a racemic     mixture, an enantiomer, an optical isomer and/or stereoisomer     thereof.

Examples of compounds of formula I-G1 are the following:

-   (1 RS,5     SR)-6-(5-phenylethynyl-pyridin-2-yl)-6-aza-bicyclo[3.2.0]heptan-7-one; -   3,3-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-azetidin-2-one; and -   (1RS,5SR)-6-(5-pyridin-3-ylethynyl-pyridin-2-yl)-6-aza-bicyclo[3.2.0]heptan-7-one.

The invention further provides compounds of formula I, wherein Y is —CH₂O—, for example

-   (RS)-6-methyl-4-(5-phenylethynyl-pyridin-2-yl)-morpholin-3-one and -   6,6-dimethyl-4-(5-phenylethynyl-pyridin-2-yl)-morpholin-3-one.

The invention further provides compounds of formula I, wherein Y is —CH₂S(O)₂—, for example 1,1-dioxo-4-(5-phenylethynyl-pyridin-2-yl)-thiomorpholin-3-one.

The invention also provides compounds of formula I, wherein m is 2, for example 7,7-dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazepan-2-one.

The invention provides ethynyl compounds of formula Ia

wherein

-   X is N or C—R⁵,     -   wherein R⁵ is hydrogen or halogen; -   Y is N—R⁶, O or CHR⁷,     -   wherein R⁶ is hydrogen or lower alkyl and R⁷ is hydrogen,         hydroxy, lower alkyl or lower alkoxy; -   R¹ is phenyl or heteroaryl, each of which is optionally substituted     by halogen, lower alkyl or lower alkoxy; -   R² and R^(2′) are each independently hydrogen, lower alkyl, or     CH₂-lower alkoxy or together with the carbon atom to which they are     attached form a C₃-C₆-cycloalkyl group; -   m is 0 or 1; when m is 1, -   R³ and R^(3′) are each independently hydrogen, lower alkyl, or     CH₂-lower alkoxy or together with the carbon atom to which they are     attached form a C₃-C₆-cycloalkyl group; and -   n is 0 or 1; when n is 1, -   R⁴ and R^(4′) are each independently hydrogen, lower alkyl, or     CH₂-lower alkoxy or together with the carbon atom to which they are     attached form a C₃-C₆-cycloalkyl group; -   or when m is 1 and n is O, R³ and R² together with the carbon atoms     to which they are attached form a C₃₋₆-cycloalkyl group; -   or when m is 0 and m is 1, R⁴ and R² together with the carbon atoms     to which they are attached form a C₃₋₆-cycloalkyl group;     or a pharmaceutically acceptable acid addition salt, racemic     mixture, an enantiomer, an optical isomer, and/or stereoisomer     thereof.

The preparation of compounds of formula I of the present invention can be carried out in sequential or convergent synthetic routes. Syntheses of the compounds of the invention are shown in the following schemes 1 to 3. The skills required for carrying out the reaction and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein before.

The compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. The reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art.

The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods, known in the art, for example by the process variant described below, which process comprises reacting a compound of formula

wherein X is a suitable leaving group which can be substituted by an acetylene moiety such as, for example a bromine or iodine atom, a trialkylstannyl group, a boronic acid or boronic ester group with a suitable aryl-acetylene of formula

to obtain a compound of formula

wherein the substituents are described above, or if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.

The preparation of compounds of formula I is further described in more detail in schemes 1 to 6 and in examples 1-174.

A ethynyl-pyridine, ethynyl-pyrimidine, ethynyl-pyrazine or ethynyl-pyridazine compound of formula I-A can be obtained by substitution of an appropriate 5-iodo-2-fluoro-pyridine, 5-iodo-2-fluoro-pyrimidine, 2-chloro-5-iodopyridazine or 2-bromo-5-iodopyrazine 1 or the like and an appropriate aminoalcohol 2 with a base such as pyridine, triethylamine, or cesium carbonate in a solvent such as NMP, pyridine, or dioxane to yield the corresponding 5-iodo-2-aminoalkoxy-adducts of formula 3, which are treated with phosgene or a phosgene equivalent such as triphosgene in presence of base such as pyridine in a solvent like dichloromethane to give the corresponding cyclized urethane- or urea-derivatives 4. Sonogashira coupling of the iodo-heteroaryl derivatives 4 with an appropriately substituted arylacetylene 5 yield the desired ethynyl compounds of general formula I-A or I-D (scheme 1).

An ethynyl-pyridine, ethynyl-pyrimidine, ethynyl-pyrazine or ethynyl-pyridazine compound of formula I-B can be obtained by reacting an appropriate 5-iodo-2-amino-pyridine- or 5-iodo-2-amino-pyrimidine-, 5-iodo-2-amino-pyrazine, or 5-iodo-2-amino-pyridazine derivative 6 or the like with an appropriately substituted anhydride 7 in a solvent such as DMF to yield the corresponding imide derivative 8, which is reduced with a reducing agent such as sodium borohydride in a solvent such as THF and/or MeOH to give the corresponding alcohol derivative 9. Reacting compound 9 with trifluoroacetic anhydride in a solvent like dichloromethane followed by reduction with triethylsilane in a solvent like TFA yields the desired amide 10. Sonogashira coupling of the amide 10 with an appropriately substituted aryl-acetylene 5 yields the desired ethynyl-compounds of formula I-B or I-E (scheme 2).

An ethynyl-pyridine, ethynyl-pyrimidine, ethynyl-pyrazine or ethynyl-pyridazine compound of formula I-C can be obtained by substitution of an appropriate 5-iodo-2-fluoro-pyridine, 5-iodo-2-fluoro-pyrimidine, 2-chloro-5-iodopyridazine or 2-bromo-5-iodopyrazine 1 or the like (1) wherein Y is a suitable leaving group which can be displaced via nucleophillic substitution by an amine such as a fluorine, chlorine, or bromine atom or an alkysulfonyl group with an appropriate diaminoalkyl derivative 11 in presence of a base such as pyridine or cesium carbonate in a solvent like NMP, pyridine, or dioxane to yield the corresponding N-heteroaryl derivative 12, which is cyclized with phosgene or a phosgene equivalent in presence of a base such as pyridine or triethylamine in a solvent like dichloromethane or THF to give the corresponding urea derivative 13 which is then coupled with an appropriately substituted aryl-acetylene 5 to yield the desired ethynyl-compound of formula I-C or I-F (scheme 3).

An ethynyl-pyridine or ethynyl-pyrimidine compound of formula I can be obtained for example by Sonogashira coupling of a 2-bromo-5-iodo-pyridine, 2-bromo-5-iodo-pyrimidine, 2-bromo-5-iodopyridazine or 2-bromo-5-iodopyrazine 1 or the like with ethynyltrimethylsilane 15 to yield the 2-bromo-5-trimethylsilanylethynyl-substituted heteroaryl derivatives 16. Substitution of 16 with an appropriate lactam, cyclic carbamate or cyclic urea derivative 17 in presence of a base such as cesium carbonate, or using xantphos and Pd₂(dba)₃ in a solvent like toluene yields the corresponding 5-trimethylsilanylethynyl derivatives 18. Sonogashira coupling with in-situ desilylation of 18 in presence of fluoride and an appropriately substituted aryl-halogenide 19 yields the desired arylethynyl-compounds of formula I (scheme 4).

An arylethynyl compound of formula I can be obtained by Sonogashira coupling of a 5-bromo- or 5-iodo-heteroaryl derivative 4, 10 or 13 (where Y═Br, I) with ethynyltrimethylsilane 15 to yield the corresponding 5-trimethylsilanylethynyl-derivatives 18. Sonogashira coupling with in-situ desilylation of 18 and an appropriately substituted aryl-halogenide 19 yields the desired ethynyl-pyridine or ethynyl-pyrimidine compounds of formula I (scheme 5).

Generally speaking, the sequence of steps used to synthesize the compounds of formula I can also be modified in certain cases, for example by first running the Sonogashira coupling with an appropriately substituted aryl- or heteroaryl-ethynyl derivative followed by the introduction of a lactam-, cyclic carbamate- or cyclic urea using procedures similar to those described in schemes 1 to 4. (scheme 6)

The compound of formula I as described herein as well as its pharmaceutically acceptable salt is used in the treatment or prevention of psychosis, epilepsy, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits, chronic and acute pain, restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia, ischemia, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments, muscle spasms, convulsions, migraine, urinary incontinence, gastrointestinal reflux disorder, liver damage or failure whether drug or disease induced, Fragile-X syndrom, Down syndrom, autism, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia, eating disorders, in particular bulimia or anorexia nervosa, and depressions, particularly for the treatment and prevention of acute and/or chronic neurological disorders, anxiety, the treatment of chronic and acute pain, urinary incontinence and obesity.

The preferred indications are schizophrenia and cognitive disorders.

Present invention further relates to the use of a compound of formula I as described herein, as well as its pharmaceutically acceptable salt, for the manufacture of a medicament, preferably for the treatment and prevention of the above-mentioned disorders.

Biological Assay and Data Intracellular Ca²⁺ Mobilization Assay

A monoclonal HEK-293 cell line stably transfected with a cDNA encoding for the human mGlu5a receptor was generated; for the work with mGlu5 Positive Allosteric Modulators (PAMs), a cell line with low receptor expression levels and low constitutive receptor activity was selected to allow the differentiation of agonistic versus PAM activity. Cells were cultured according to standard protocols (Freshney, 2000) in Dulbecco's Modified Eagle Medium with high glucose supplemented with 1 mM glutamine, 10% (vol/vol) heat-inactivated bovine calf serum, Penicillin/Streptomycin, 50 μg/ml hygromycin and 15 μg/ml blasticidin (all cell culture reagents and antibiotics from Invitrogen, Basel, Switzerland).

About 24 hrs before an experiment, 5×10⁴ cells/well were seeded in poly-D-lysine coated, black/clear-bottomed 96-well plates. The cells were loaded with 2.5 μM Fluo-4AM in loading buffer (1×HBSS, 20 mM HEPES) for 1 hr at 37° C. and washed five times with loading buffer. The cells were transferred into a Functional Drug Screening System 7000 (Hamamatsu, Paris, France), and 11 half logarithmic serial dilutions of test compound at 37° C. were added and the cells were incubated for 10-30 min. with on-line recording of fluorescence. Following this pre-incubation step, the agonist L-glutamate was added to the cells at a concentration corresponding to EC₂₀ (typically around 80 μM) with on-line recording of fluorescence; in order to account for day-to-day variations in the responsiveness of cells, the EC₂₀ of glutamate was determined immediately ahead of each experiment by recording of a full dose-response curve of glutamate.

Responses were measured as peak increase in fluorescence minus basal (i.e. fluorescence without addition of L-glutamate), normalized to the maximal stimulatory effect obtained with saturating concentrations of L-glutamate. Graphs were plotted with the % maximal stimulatory using XLfit, a curve fitting program that iteratively plots the data using Levenburg Marquardt algorithm. The single site competition analysis equation used was y=A+((B−A)/(1+((x/C)D))), where y is the % maximal stimulatory effect, A is the minimum y, B is the maximum y, C is the EC₅₀, x is the log 10 of the concentration of the competing compound and D is the slope of the curve (the Hill Coefficient). From these curves the EC₅₀ (concentration at which half maximal stimulation was achieved), the Hill coefficient as well as the maximal response in % of the maximal stimulatory effect obtained with saturating concentrations of L-glutamate were calculated.

Positive signals obtained during the pre-incubation with the PAM test compounds (i.e. before application of an EC₂₀ concentration of L-glutamate) were indicative of an agonistic activity, the absence of such signals were demonstrating the lack of agonistic activities. A depression of the signal observed after addition of the EC₂₀ concentration of L-glutamate was indicative of an inhibitory activity of the test compound.

In the list of examples below are shown the corresponding results for compounds which all have

EC₅₀<300 nM.

The compounds of formula (I) and pharmaceutically acceptable salts thereof can be used as medicaments, e.g. in the form of pharmaceutical compositions. The pharmaceutical compositions can be administered orally, e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injectable solutions.

The present invention also provides pharmaceutical compositions containing compounds of the invention, for example, compounds of formula I or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier. Such pharmaceutical compositions can be in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions. The pharmaceutical compositions also can be in the form of suppositories or injectable solutions.

The pharmaceutical compositions of the invention, in addition to one or more compounds of the invention, contain a pharmaceutically acceptable carrier. Suitable pharmaceutically acceptable carriers include pharmaceutically inert, inorganic or organic carriers. lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like, for example, as such carriers for tablets, coated tablets, dragées and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of formula (I), but as a rule are not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

In addition, the pharmaceutical compositions can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

As mentioned earlier, medicaments containing a compound of formula (I) or pharmaceutically acceptable salts thereof and a therapeutically inert excipient are also an object of the present invention, as is a process for the production of such compositions which comprises bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers.

As further mentioned earlier, the use of the compounds of formula (I) for the preparation of pharmaceutical compositions useful in the prevention and/or the treatment of the above-recited diseases is also an aspect of the present invention.

The dosage at which compounds of the invention can be administered can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/kg/day being preferred for all of the indications described. The daily dosage for an adult human being weighing 70 kg accordingly lies between 0.7-1400 mg per day, preferably between 7 and 700 mg per day.

Preparation of pharmaceutical compositions comprising compounds of the invention: Tablets of the following composition are produced in a conventional manner:

mg/Tablet Active ingredient 100 Powdered. lactose 95 White corn starch 35 Polyvinylpyrrolidone 8 Na carboxymethylstarch 10 Magnesium stearate 2 Tablet weight 250

LIST OF EXAMPLES

EC₅₀ (nM) Eff. Ex. Structure Name mGlu5PAM (%) 1

3-(3-Fluoro-5- phenylethynyl-pyridin- 2-yl)-5,5-dimethyl- oxazolidin-2-one 30 68 2

(5RS)-5- Methoxymethyl-3-(5- phenylethynyl-pyridin- 2-yl)-oxazolidin-2-one 47 34 3

 

(5R or 5S)-5- Methoxymethyl-3-(5- phenylethynyl-pyridin- 2-yl)-oxazolidin-2-one 18 46 4

 

(5S or 5R)-5- Methoxymethyl-3-(5- phenylethynyl-pyridin- 2-yl)-oxazolidin-2- 278 98 5

5,5-Dimethyl-3-(5- phenylethynyl-pyridin- 2-yl)-oxazolidin-2-one 7 77 6

3-[5-(3-Fluoro- phenylethynyl)-pyridin- 2-yl]-5,5-dimethyl- oxazolidin-2-one 9 46 7

5,5-Dimethyl-3-(5- pyridin-3-ylethynyl- pyridin-2-yl)- oxazolidin-2-one 33 39 8

(5RS)-5-tert-Butyl-3- (5-phenylethynyl- pyridin-2-yl)- oxazolidin-2-one 17 62 9

6-(5-Phenylethynyl- pyridin-2-yl)-4-oxa-6- aza-spiro[2.4]heptan-5- one 15 83 10

7-(5-Phenylethynyl- pyridin-2-yl)-5-oxa-7- aza-spiro[3.4]octan-6- one 25 109 11

3-(5-Phenylethynyl- pyridin-2-yl)-1-oxa-3- aza-spiro[4.4]nonan-2- one 39 52 12

3-(5-Phenylethynyl- pyridin-2-yl)-1-oxa-3- aza-spiro[4.5]decan-2- one 67 80 13

4,4-Dimethyl-1-(5- phenylethynyl-pyridin- 2-yl)-pyrrolidin-2-one 37 129 14

(3RS)-3-Hydroxy-4,4- dimethyl-1-(5- phenylethynyl-pyridin- 2-yl)-pyrrolidin-2-one 388 114 15

4,4-Dimethyl-1-(5- phenylethynyl-pyridin- 2-yl)-imidazolidin-2- one 130 101 16

3,4,4-Trimethyl-1-(5- phenylethynyl-pyridin- 2-yl)-imidazolidin-2- one 35 103 17

3-Ethyl-4,4-dimethyl- 1-(5-phenylethynyl- pyridin-2-yl)- imidazolidin-2-one 66 103 18

3-Isopropyl-4,4- dimethyl-1-(5- phenylethynyl-pyridin- 2-yl)-imidazolidin-2- one 39 133 19

(5RS)-5-tert-Butyl-5- methyl-3-(5- phenylethynyl-pyridin- 2-yl)-oxazolidin-2-one 27 85 20

5,5-Dimethyl-3-(5- phenylethynyl-pyridin- 2-yl)-[1,3]oxazinan-2- one 27 135 21

1-(3-Fluoro-5- phenylethynyl-pyridin- 2-yl)-4,4-dimethyl- pyrrolidin-2-one 30 128 22

(3aRS,6aSR)-3-(5- Phenylethynyl-pyridin- 2-yl)-hexahydro- cyclopentaoxazol-2- one 14 74 23

(3aRS,6aSR)-3-(5- Pyridin-3-ylethynyl- pyridin-2-yl)- hexahydro- cyclopentaoxazol-2- one 12 92 24

(3aRS,6aSR)-3-[5-(5- Fluoro-pyridin-3- ylethynyl)-pyridin-2- yl]-hexahydro- cyclopentaoxazol-2- one 35 73 25

5,5-Dimethyl-1-(5- phenylethynyl-pyridin- 2-yl)-tetrahydro- pyrimidin-2-one 69 148 26

1,5,5-Trimethyl-3-(5- phenylethynyl-pyridin- 2-yl)-tetrahydro- pyrimidin-2-one 33 131 27

(RS)-4,5,5-Trimethyl- 3-(5-phenylethynyl- pyridin-2-yl)- oxazolidin-2-one 15 61 28

4,4,5,5-Tetramethyl- 3-(5-phenylethynyl- pyridin-2-yl)- oxazolidin-2-one 48 31 29

3-[5-(5-Fluoro-pyridin- 3-ylethynyl)-pyridin-2- yl]-5,5-dimethyl- oxazolidin-2-one 15 45 30

5,5-Dimethyl-3-(5- pyrimidin-5- ylethynyl-pyridin-2- yl)-oxazolidin-2-one 80 43 31

5,5-Dimethyl-3-[5-(1- methyl-1H-pyrazol-4- ylethynyl)-pyridin-2- yl]-oxazolidin-2-one 26 55 32

3-[5-(4-Fluoro- phenylethynyl)- pyridin-2-yl]-5,5- dimethyl-oxazolidin- 2-one 19 60 33

3-[5-(3,4-Difluoro- phenylethynyl)-pyridin- 2-yl]-5,5-dimethyl- oxazolidin-2-one 32 44 34

3-[5-(2,5-Difluoro- phenylethynyl)- pyridin-2-yl]- 5,5-dimethyl- oxazolidin-2-one 11 38 35

3-[5-(6-Fluoro-pyridin- 3-ylethynyl)-pyridin-2- yl]-5,5-dimethyl- oxazolidin-2-one 54 52 36

6-(5-Pyridin-3- ylethynyl-pyridin-2- yl)-4-oxa-6-aza- spiro[2.4]heptan-5- one 58 80 37

1-[5-(5-Fluoro-pyridin- 3-ylethynyl)-pyridin-2- yl]-4,4-dimethyl- pyrrolidin-2-one 22 96 38

4,4-Dimethyl-1-(5- pyridin-3-ylethynyl- pyridin-2-yl)- pyrrolidin-2-one 33 147 39

1-[5-(5-Chloro-pyridin- 3-ylethynyl)-pyridin-2- yl]-4,4-dimethyl- pyrrolidin-2-one 48 98 40

1-[5-(3-Fluoro- phenylethynyl)-pyridin- 2- yl]-4,4-dimethyl- pyrrolidin-2-one 15 100 41

4,4-Dimethyl-1-(3- methyl-5- phenylethynyl-pyridin- 2-yl)-pyrrolidin-2-one 58 89 42

5,5-Dimethyl-5′- phenylethynyl-3,4,5,6- tetrahydro- [1,2′]bipyridinyl-2-one 16 139 43

5′-(3-Fluoro- phenylethynyl)-5,5- dimethyl-3,4,5,6- tetrahydro- [1,2′]bipyridinyl-2-one 12 100 44

1-Methyl-3-(5- phenylethynyl-pyridin- 2-yl)-1,3-diaza- spiro[4.4]nonan-2-one 29 92 45

(RS)-4-Cyclopentyl-3- methyl-1-(5- phenylethynyl-pyridin- 2-yl)-imidazolidin-2- one 57 97 46

(1RS,5SR)-6-(5- Phenylethynyl-pyridin- 2-yl)-6-aza- bicyclo[3.2.0]heptan-7- one 26 27 47

(6SR,7RS)-3-(5- Phenylethynyl-pyridin- 2-yl)-hexahydro- benzooxazol-2-one 36 109 48

3,4,4-Trimethyl-1-(5- pyridin-3-ylethynyl- pyridin-2-yl)- imidazolidin-2-one 14 89 49

1-[5-(5-Fluoro-pyridin- 3-ylethynyl)-pyridin-2- yl]-3,4,4-trimethyl- imidazolidin-2-one 37 91 50

3,4,4-Trimethyl-1-[5- (1-methyl-1H-pyrazol- 4-ylethynyl)-pyridin-2- yl]-imidazolidin-2-one 27 41 51

1-[5-(5-Chloro-pyridin- 3-ylethynyl)-pyridin-2- yl]-3,4,4-trimethyl- imidazolidin-2-one 29 45 52

3,4,4-Trimethyl-1-(5- pyridazin-4-ylethynyl- pyridin-2-yl)- imidazolidin-2-one 34 32 53

1-[5-(3-Fluoro- phenylethynyl)-pyridin- 2-yl]-3,4,4-trimethyl- imidazolidin-2-one 29 103 54

1-[5-(3-Chloro- phenylethynyl)-pyridin- 2-yl]-3,4,4-trimethyl- imidazolidin-2-one 32 47 55

3,4,4-Trimethyl-1-(5- pyrimidin-5-ylethynyl- pyridin-2-yl)- imidazolidin-2-one 54 110 56

3,4,4-Trimethyl-1-(5- m-tolylethynyl-pyridin- 2-yl)-imidazolidin-2- one 87 56 57

1-[5-(4-Fluoro- phenylethynyl)-pyridin- 2-yl]-3,4,4-trimethyl- imidazolidin-2-one 35 78 58

(RS)-2-(5-Phenylethynyl- pyridin-2-yl)-hexahydro- imidazo[1,5-a]pyridin-3- one 33 43 59

2-(5-Phenylethynyl- pyridin-2-yl)-2-aza- spiro[4.4]nonan-3-one 16 81 60

(RS)-3-Methoxy-4,4- dimethyl-1-(5- phenylethynyl-pyridin- 2-yl)-pyrrolidin-2-one 35 89 61

 

(R or S)-3-Methoxy- 4,4-dimethyl-1-(5- phenylethynyl-pyridin- 2-yl)-pyrrolidin-2-one 75 70 62

 

(S or R)-3-Methoxy- 4,4-dimethyl-1-(5- phenylethynyl-pyridin- 2-yl)-pyrrolidin-2-one 12 86 63

(RS)-1-[5-(5-Chloro- pyridin-3-ylethynyl)- pyridin-2-yl]-3- methoxy-4,4-dimethyl- pyrrolidin-2-one 70 99 64

(RS)-3-Methoxy-4,4- dimethyl-1-(5-m- tolylethynyl-pyridin-2- yl)-pyrrolidin-2-one 87 56 65

(RS)-1-[5-(3-Fluoro- phenylethynyl)-pyridin- 2-yl]-3-methoxy-4,4- dimethyl-pyrrolidin-2- one 43 91 66

(RS)-1-[5-(4-Fluoro- phenylethynyl)-pyridin- 2-yl]-3-methoxy-4,4- dimethyl-pyrrolidin-2- one 75 87 67

3,4,4-Trimethyl-1-(5- phenylethynyl-pyridin- 2-yl)-tetrahydro- pyrimidin-2-one 15 81 68

1-[5-(2,5-Difluoro- phenylethynyl)-pyridin- 2-yl]-3,4,4-trimethyl- tetrahydro-pyrimidin-2- one 41 79 69

1-[5-(4-Fluoro- phenylethynyl)-pyridin- 2-yl]-3,4,4-trimethyl- tetrahydro-pyrimidin-2- one 49 107 70

(RS)-2-(5-Pyridin-3- ylethynyl-pyridin-2-yl)- hexahydro- imidazo[1,5-a]pyridin- 3-one 74 51 71

(RS)-2-[5-(3-Fluoro- phenylethynyl)-pyridin- 2-yl]-hexahydro- imidazo[1,5-a]pyridin- 3-one 17 41 72

6,6-Dimethyl-3-(5- phenylethynyl-pyridin- 2-yl)-[1,3]oxazinan-2- one 10 86 73

6,6-Dimethyl-3-(5- pyridin-3-ylethynyl- pyridin-2-yl)- [1,3]oxazinan-2-one 59 98 74

3-[5-(5-Fluoro-pyridin- 3-ylethynyl)-pyridin-2- yl]-6,6-dimethyl- [1,3]oxazinan-2-one 59 108 75

3-[5-(5-Chloro-pyridin- 3-ylethynyl)-pyridin-2- yl]-6,6-dimethyl- [1,3]oxazinan-2-one 27 87 76

3-[5-(3-Fluoro- phenylethynyl)-pyridin- 2-yl]-6,6-dimethyl- [1,3]oxazinan-2-one 13 124 77

3-[5-(3-Chloro- phenylethynyl)-pyridin- 2-yl]-6,6-dimethyl- [1,3]oxazinan-2-one 12 72 78

6,6-Dimethyl-3-(5-m- tolylethynyl-pyridin-2- yl)-[1,3]oxazinan-2-one 24 72 79

3-[5-(4-Fluoro- phenylethynyl)-pyridin- 2-yl]-6,6-dimethyl- [1,3]oxazinan-2-one 22 85 80

3-[5-(3,4-Difluoro- phenylethynyl)-pyridin- 2-yl]-6,6-dimethyl- [1,3]oxazinan-2-one 37 69 81

3-[5-(2,5-Difluoro- phenylethynyl)-pyridin- 2-yl]-6,6-dimethyl- [1,3]oxazinan-2-one 12 95 82

6-(5-Phenylethynyl- pyridin-2-yl)-2-oxa-6- aza-spiro[3.4]octan-7- one 57 72 83

(RS)-4-Cyclopropyl-3- methyl-1-(5- phenylethynyl-pyridin- 2-yl)-imidazolidin-2- one 53 86 84

(3aSR,7aRS)- (3aRS,7RS)-1-Methyl- 3-(5-phenylethynyl- pyridin-2-yl)- octahydro- benzoimidazol-2-one 11 64 85

(3aSR,7aRS)- (3aRS,7RS)-1-Methyl- 3-(5-pyridin-3- ylethynyl-pyridin-2-yl)- octahydro- benzoimidazol-2-one 27 49 86

(3aSR,7aRS)- (3aRS,7RS)-1-[5-(5- Fluoro-pyridin-3- ylethynyl)-pyridin-2- yl]-3-methyl-octahydro- benzoimidazol-2-one 32 52 87

4,4-Dimethyl-5′- phenylethynyl-3,4,5,6- tetrahydro- [1,2′]bipyridinyl-2-one 12 89 88

5′-(3-Fluoro- phenylethynyl)-4,4- dimethyl-3,4,5,6- tetrahydro- [1,2′]bipyridinyl-2-one 19 110 89

5′-(3-Chloro- phenylethynyl)-4,4- dimethyl-3,4,5,6- tetrahydro- [1,2′]bipyridinyl-2-one 25 78 90

5′-(5-Chloro-pyridin-3- ylethynyl)-4,4-dimethyl- 3,4,5,6-tetrahydro- [1,2′]bipyridinyl-2-one 66 90 91

5′-(4-Fluoro- phenylethynyl)-4,4- dimethyl-3,4,5,6- tetrahydro- [1,2′]bipyridinyl-2-one 67 89 92

5′-(2,5-Difluoro- phenylethynyl)-4,4- dimethyl-3,4,5,6- tetrahydro- [1,2′]bipyridinyl-2-one 32 84 93

7,7-Dimethyl-3-(5- phenylethynyl-pyridin- 2-yl)-[1,3]oxazepan-2- one 36 104 94

(3aSR,7aRS)- (3aRS,7RS)-1-(5- Phenylethynyl-pyridin- 2-yl)-hexahydro- pyrano[4,3-d]oxazol-2- one 60 84 95

(RS)-5-Hydroxy-6,6- dimethyl-3-(5- phenylethynyl-pyridin- 2-yl)-[1,3]oxazinan-2- one 47 118 96

4-Methyl-6-(5- phenylethynyl-pyridin- 2-yl)-4,6-diaza- spiro[2.4]heptan-5-one 35 98 97

3,3-Dimethyl-1-(5- phenylethynyl-pyridin- 2-yl)-azetidin-2-one 36 71 98

(1RS,5SR)-6-(5- Pyridin-3-ylethynyl- pyridin-2-yl)-6-aza- bicyclo[3.2.0]heptan- 7-one 39 73 99

(3aSR,7aRS)- (3aRS,7RS)-1-Ethyl- 3-(5-phenylethynyl- pyridin-2-yl)- octahydro- benzoimidazol-2-one 18 90 100

(3aSR,7aRS)- (3aRS,7RS)-1-Ethyl-3- (5-pyridin-3-ylethynyl- pyridin-2-yl)-octahydro- benzoimidazol-2-one 69 64 101

(3aSR,7aRS)- (3aRS,7RS)-1- Isopropyl-3-(5- phenylethynyl-pyridin- 2-yl)-octahydro- benzoimidazol-2-one 39 77 102

(4aRS,7aSR)-3-(5- Phenylethynyl-pyridin- 2-yl)-hexahydro-cyclo- penta[e][1,3]oxazin- 2-one 43 115 103

(4aRS,7aRS)-3-(5- Phenylethynyl-pyridin- 2-yl)-hexahydro- cyclo- penta[e] [1,3]oxazin- 2-one 27 123 104

(RS)-5,6,6-Trimethyl-3- (5-phenylethynyl- pyridin-2-yl)- [1,3]oxazinan-2-one 42 109 105

(RS)-6- Methoxymethyl-3-(5- phenylethynyl-pyridin- 2-yl)-[1,3]oxazinan-2- one 68 51 106

(3aRS,6aSR)-1-Methyl- 3-(5-(phenylethynyl) pyridin-2-yl)hexa- hydrocyclopenta[d] imidazol-2(1H)-one 30 42 107

(RS)-4-tert-Butyl-3- methyl-1-(5- phenylethynyl-pyridin- 2-yl)-imidazolidin-2- one 59 106 108

1-[5-(3-Fluoro- phenylethynyl)-3- methyl-pyridin-2-yl]- 3,4,4-trimethyl- imidazolidin-2-one 102 115 109

(3aRS, 6aSR)-1-[5-(3- Fluoro-phenylethynyl)- pyridin-2-yl]-3-methyl- hexahydro-cyclopenta- imidazol-2-one 18 37 110

1-[3-Fluoro-5-(4- fluoro-phenylethynyl)- pyridin-2-yl]-3,4,4- trimethyl-imidazolidin- 2-one 96 117 111

1-[3-Fluoro-5-(3- fluoro-phenylethynyl)- pyridin-2-yl]-3,4,4- trimethyl-imidazolidin- 2-one 32 107 112

6-[5-(4-Fluoro- phenylethynyl)-pyridin- 2-yl]-4-methyl-4,6- diaza-spiro[2.4]heptan- 5-one 80 89 113

6-[5-(3-Fluoro- phenylethynyl)-pyridin- 2-yl]-4-methyl-4,6- diaza-spiro[2.4]heptan- 5-one 51 75 114

(RS)-5-Methoxy-6,6- dimethyl-3-(5- phenylethynyl-pyridin- 2-yl)-[1,3]oxazinan- 2-one 22 57 115

4,4-Dimethyl-1-(5- phenylethynyl- pyrimidin-2-yl)- pyrrolidin-2-one 13 109 116

5,5-Dimethyl-1-(5- phenylethynyl- pyrimidin-2-yl)- piperidin-2-one 41 101 117

2-(5-Phenylethynyl- pyrimidin-2-yl)-2-aza- spiro[4.4]nonan-3-one 44 84 118

1-[5-(3-Fluoro- phenylethynyl)- pyrimidin-2-yl]-4,4- dimethyl-pyrrolidin-2- one 13 78 119

1-[5-(3-Chloro- phenylethynyl)- pyrimidin-2-yl]-4,4- dimethyl-pyrrolidin-2- one 11 26 120

1-[5-(4-Fluoro- phenylethynyl)- pyrimidin-2-yl]-4,4- dimethyl-pyrrolidin-2- one 92 81 121

1-[5-(2,5-Difluoro- phenylethynyl)- pyrimidin-2-yl]-4,4- dimethyl-pyrrolidin-2- one 41 70 122

3,4,4-Trimethyl-1- (5-phenylethynyl- pyrimidin-2-yl)- imidazolidin-2-one 11 36 123

1-[5-(3-Fluoro- phenylethynyl)- pyrimidin-2-yl]-3,4,4- trimethyl-imidazolidin- 2-one 18 30 124

1-[5-(2,5-Difluoro- phenylethynyl)- pyrimidin-2-yl]-3,4,4- trimethyl-imidazolidin- 2-one 7 43 125

1-[5-(4-Fluoro- phenylethynyl)- pyrimidin-2-yl]-3,4,4- trimethyl-imidazolidin- 2-one 13 44 126

1-[5-(3,4-Difluoro- phenylethynyl)- pyrimidin-2-yl]-3,4,4- trimethyl-imidazolidin- 2-one 23 36 127

(RS)-3-Methoxy-4,4- dimethyl-1-(5- phenylethynyl- pyrimidin-2-yl)- pyrrolidin-2-one 29 94 128

 

(R or S)-3-Methoxy- 4,4-dimethyl-1-(5- phenylethynyl- pyrimidin-2-yl)- pyrrolidin-2-one 46 54 129

 

(S or R)-3-Methoxy- 4,4-dimethyl-1-(5- phenylethynyl- pyrimidin-2-yl)- pyrrolidin-2-one 18 90 130

(RS)-1-[5-(3-Fluoro- phenylethynyl)- pyrimidin-2-yl]-3- methoxy-4,4-dimethyl- pyrrolidin-2-one 41 74 131

 

(R or S)-1-[5-(3-Fluoro- phenylethynyl)- pyrimidin-2-yl]-3- methoxy-4,4-dimethyl- pyrrolidin-2-one 35 48 132

 

(S or R)-1-[5-(3-Fluoro- phenylethynyl)- pyrimidin-2-yl]-3- methoxy-4,4-dimethyl- pyrrolidin-2-one 21 69 133

 

(R or S)-1-[5-(2,5- Difluoro- phenylethynyl)- pyrimidin-2-yl]-3- methoxy-4,4-dimethyl- pyrrolidin-2-one 57 49 134

4,4-Dimethyl-1-(5- phenylethynyl- pyrimidin-2-yl)- piperidin-2-one 42 90 135

1-[5-(3-Fluoro- phenylethynyl)- pyrimidin-2-yl]-4,4- dimethyl-piperidin-2- one 35 47 136

1-[5-(2,5-Difluoro- phenylethynyl)- pyrimidin-2-yl]-4,4- dimethyl-piperidin-2- one 31 49 137

3,4,4-Trimethyl-5′- phenylethynyl-3,4,5,6- tetrahydro- [1,2′]bipyrimidinyl-2- one 66 74 138

5′-(3-Fluoro- phenylethynyl)-3,4,4- trimethyl-3,4,5,6- tetrahydro- [1,2']bipyrimidinyl-2- one 60 67 139

5′-(2,5-Difluoro- phenylethynyl)-3,4,4- trimethyl-3,4,5,6- tetrahydro- [1,2′]bipyrimidinyl-2- one 57 54 140

3-Isopropyl-4,4- dimethyl-1-(5- phenylethynyl- pyrimidin-2-yl)- imidazolidin-2-one 28 58 141

1-[5-(3-Fluoro- phenylethynyl)- pyrimidin-2-yl]-3- isopropyl-4,4-dimethyl- imidazolidin-2-one 28 39 142

1-[5-(4-Fluoro- phenylethynyl)- pyrimidin-2-yl]-3- isopropyl-4,4-dimethyl- imidazolidin-2-one 78 74 143

1-[5-(4-Fluoro- phenylethynyl)- pyrimidin-2-yl]-3-ethyl- 4,4-dimethyl- imidazolidin-2-one 47 68 144

1-[5-(3-Fluoro- phenylethynyl)- pyrimidin-2-yl]-3- ethyl-4,4-dimethyl- imidazolidin-2-one 31 58 145

(RS)-5,6,6-Trimethyl- 3-(5-phenylethynyl- pyrimidin-2-yl)- [1,3]oxazinan-2-one 38 93 146

(RS)-3-[5-(2,5-Difluoro- phenylethynyl)- pyrimidin-2-yl]-5,6,6- trimethyl- [1,3]oxazinan-2-one 69 64 147

4-Methyl-6-(5- phenylethynyl- pyrimidin-2-yl)-4,6- diaza-spiro[2.4]heptan- 5-one 25 36 148

(RS)-3-[5-(3-Fluoro- phenylethynyl)- pyrimidin-2-yl]-5,6,6- trimethyl- [1,3]oxazinan-2-one 39 75 149

(RS)-3-[5-(4-Fluoro- phenylethynyl)- pyrimidin-2-yl]-5,6,6- trimethyl- [1,3]oxazinan-2-one 114 78 150

4,4-dimethyl-1-(6- (phenylethynyl) pyridazin-3-yl) pyrrolidin-2-one 21 113 151

4,4-dimethyl-1-(6- (phenylethynyl)pyridazin- 3-yl)piperidin-2-one 19 130 152

5,5-dimethyl-3-(6- (phenylethynyl)pyridazin- 3-yl)oxazolidin-2-one 15 112 153

6,6-dimethyl-3-(6- (phenylethynyl)pyridazin- 3-yl)-1,3-oxazinan-2- one 14 86 154

3,4,4-trimethyl-1-(6- (m- tolylethynyl)pyridazin- 3-yl)imidazolidin-2-one 61 108 155

1-(6-((3- chlorophenyl)ethynyl) pyridazin-3-yl)-3,4,4- trimethylimidazolidin- 2-one 73 95 156

3,4,4-trimethyl-1-(5- (phenylethynyl)pyrazin- 2-yl)imidazolidin-2-one 24 58 157

3,4,4-trimethyl-1-(5- (pyridin-3- ylethynyl)pyrazin-2- yl)imidazolidin-2-one 206 34 158

1-(5-((3- fluorophenyl)ethynyl) pyrazin-2-yl)-3,4,4- trimethylimidazolidin- 2-one 46 36 159

1-[5-(4-Fluoro- phenylethynyl)-pyrazin- 2-yl]-3,4,4-trimethyl- imidazolidin-2-one 49 49 160

1-(5-((3- fluorophenyl)ethynyl) pyrazin-2-yl)-4,4- dimethylpyrrolidin-2- one 29 39 161

1-(5-((3- fluorophenyl)ethynyl) pyrazin-2-yl)-4,4- dimethylpiperidin-2-one 29 68 162

4,4-dimethyl-1-(5- (pyridin-3- ylethynyl)pyrazin-2- yl)piperidin-2-one 681 76 163

4,4-dimethyl-1-(5- (phenylethynyl)pyrazin- 2-yl)piperidin-2-one 69 74 164

4,4-dimethyl-1-(5- (phenylethynyl)pyrazin- 2-yl)tetrahydro- pyrimidin-2(1H)-one 329 89 165

3,4,4-trimethyl-1-(5- (phenylethynyl)pyrazin- 2-yl)tetrahydro- pyrimidin-2(1H)-one 36 55 166

1-(5-((3- fluorophenyl)ethynyl) pyrazin-2-yl)-4,4- dimethyltetrahydro- pyrimidin-2(1H)-one 140 56 167

1-(5-((3- fluorophenyl)ethynyl) pyrazin-2-yl)-3,4,4- trimethyltetrahydro- pyrimidin-2(1H)-one 26 54 168

6,6-dimethyl-3-(5- (phenylethynyl)pyrazin- 2-yl)-1,3-oxazinan-2- one 15 41 169

(RS)-3-[5-(3-Fluoro- phenylethynyl)-pyridin- 2-yl]-5-methoxy-6,6- dimethyl- [1,3]oxazinan-2-one 13 52 170

(3aRS,6aSR)-1-Methyl- 3-(6-phenylethynyl- pyridazin-3-yl)- hexahydro- cyclopentaimidazol-2- one 13 105 171

(RS)-6-Methyl-4-(5- phenylethynyl-pyridin- 2-yl)-morpholin-3-one 88 73 172

6,6-Dimethyl-4-(5- phenylethynyl-pyridin- 2-yl)-morpholin-3-one 29 82 173

1,1-Dioxo-4-(5- phenylethynyl-pyridin- 2-yl)-thiomorpholin-3- one 29 82 174

(3aRS,6aSR)-1-[6-(3- Fluoro-phenylethynyl)- pyridazin-3-yl]-3- methyl-hexahydro- cyclopentaimidazol-2- one 12 56

EXPERIMENTAL SECTION Example 1 3-(3-Fluoro-5-phenylethynyl-pyridin-2-yl)-5,5-dimethyl-oxazolidin-2-one

Step 1: 1-(3-Fluoro-5-iodo-pyridin-2-ylamino)-2-methyl-propan-2-ol

2,3-Difluoro-5-iodopyridine (500 mg, 2.07 mmol) was dissolved in NMP (500 μl) and pyridine (201 μl, 2.49 mmol, 1.2 equiv.) and 1-amino-2-methylpropan-2-ol (555 mg, 6.22 mmol, 3 equiv.) were added at room temperature. The mixture was stirred for 16 hours at 100° C. The reaction mixture was cooled and extracted with saturated NaHCO₃ solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 100:0. The desired 1-(3-fluoro-5-iodopyridin-2-ylamino)-2-methylpropan-2-ol (590 mg, 1.9 mmol, 91.7% yield) was obtained as a colorless oil, MS: m/e=311.0 (M+H⁺).

Step 2: 3-(3-Fluoro-5-iodopyridin-2-yl)-5,5-dimethyloxazolidin-2-one

(580 mg, 1.87 mmol) 1-(3-Fluoro-5-iodopyridin-2-ylamino)-2-methylpropan-2-ol (Example 1, step 1) was dissolved in dichloromethane (10 ml) and pyridine (300 μl, 3.74 mmol, 2 equiv.) was added at room temperature. The mixture was cooled to 0-5° C. and phosgene (20% in toluene) (1.19 ml, 2.24 mmol, 1.2 equiv.) was added dropwise over a period of 15 min at 0-5° C. The mixture was stirred for 1 hour at 0-5° C. The reaction mixture was extracted with saturated NaHCO₃ solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with a heptane:ethyl acetate gradient 100:0 to 50:50. The desired 3-(3-fluoro-5-iodopyridin-2-yl)-5,5-dimethyloxazolidin-2-one (500 mg, 1.49 mmol, 79.5% yield) was obtained as a white solid, MS: m/e=337.0 (M+H⁺).

Step 3: 3-(3-Fluoro-5-phenylethynyl-pyridin-2-yl)-5,5-dimethyl-oxazolidin-2-one

Bis-(triphenylphosphine)-palladium(II)dichloride (12.5 mg, 17.9 μmol, 0.05 equiv.) was dissolved in 1 ml DMF. (120 mg, 357 μmol) 3-(3-Fluoro-5-iodopyridin-2-yl)-5,5-dimethyloxazolidin-2-one (Example 1, step 2) and phenylacetylene (72.9 mg, 78.4 μl, 714 μmol, 2 equiv.) were added at room temperature. Triethylamine (108 mg, 149 μl, 1.07 mmol, 3 equiv.), triphenylphosphine (2.81 mg, 10.7 μmol, 0.03 equiv.) and copper(I)iodide (2.04 mg, 10.7 μmol, 0.03 equiv.) were added and the mixture was stirred for 3 hours at 70° C. The reaction mixture was cooled and extracted with saturated NaHCO₃ solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 40:60. The desired 3-(3-fluoro-5-(phenylethynyl)pyridin-2-yl)-5,5-dimethyloxazolidin-2-one (96 mg, 309 μmol, 86.6% yield) was obtained as a yellow solid, MS: m/e=311.2 (M+H⁺).

Example 2 (5RS)-5-Methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one

The title compound, a light brown solid, MS: m/e=309.1 (M+H⁺), was prepared using a procedure similar to that described in Example 1, step 3 from 3-(5-bromo-pyridin-2-yl)-5-methoxymethyl-oxazolidin-2-one (CAS 170011-45-7) and phenylacetylene.

Example 3 (5R or 5S)-5-Methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one

The title compound, a white solid, MS: m/e=309.1 (M+H⁺), was prepared by separation of (5RS)-5-methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one (Example 2) using a chiral column (chiralpak AD with heptane:isopropanol 80:20 as solvent).

Example 4 (5S or 5R)-5-Methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one

The title compound, a white solid, MS: m/e=309.1 (M+H⁺), was prepared by separation of (5RS)-5-methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one (Example 2) using a chiral column (chiralpak AD with heptane:isopropanol 80:20 as solvent).

Example 5 5,5-Dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one

Step 1: 3-(5-Iodo-pyridin-2-yl)-5,5-dimethyl-oxazolidin-2-one

The title compound was obtained as a white solid, MS: m/e=292.9 (M+H⁺), using procedures similar to those described in Example 1, step 1 and step 2 from 2-fluoro-5-iodopyridine and 1-amino-2-methylpropan-2-ol.

Step 2: 5,5-Dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one

The title compound was obtained as a white solid, MS: m/e=293.0 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from 3-(5-iodo-pyridin-2-yl)-5,5-dimethyl-oxazolidin-2-one (Example 5, step 1) and phenylacetylene.

Example 6 3-[5-(3-Fluoro-phenylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one

The title compound was obtained as a white solid, MS: m/e=311.2 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from 3-(5-iodo-pyridin-2-yl)-5,5-dimethyl-oxazolidin-2-one (Example 5, step 1) and 3-fluorophenylacetylene.

Example 7 5,5-Dimethyl-3-(5-pyridin-3-ylethynyl-pyridin-2-yl)-oxazolidin-2-one

The title compound was obtained as a white solid, MS: m/e=294.1 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from 3-(5-iodo-pyridin-2-yl)-5,5-dimethyl-oxazolidin-2-one (Example 5, step 1) and 3-ethynyl-pyridine.

Example 8 (5RS)-5-tert-Butyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one

Step 1: (5RS)-5-tert-Butyl-3-(5-iodo-pyridin-2-yl)-oxazolidin-2-one

The title compound was obtained as a white solid, MS: m/e=346.9 (M+H⁺), using procedures similar to those described in Example 1, step 1 and step 2 from 2-fluoro-5-iodopyridine and (rac)-1-amino-3,3-dimethylbutan-2-ol hydrochloride.

Step 2: (5RS)-5-tert-Butyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one

The title compound was obtained as a white solid, MS: m/e=321.2 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from (5RS)-5-tert-butyl-3-(5-iodo-pyridin-2-yl)-oxazolidin-2-one (Example 8, step 1) and phenylacetylene.

Example 9 6-(5-Phenylethynyl-pyridin-2-yl)-4-oxa-6-aza-spiro[2.4]heptan-5-one

The title compound was obtained as a colourless solid, MS: m/e=291.2 (M+H⁺), using procedures similar to those described in Example 1 starting from 2-fluoro-5-bromopyridine, 1-aminomethyl-cyclopropanol (Russian J. Org. Chem. 2001, 37, 1238) and phenylacetylene.

Example 10 7-(5-Phenylethynyl-pyridin-2-yl)-5-oxa-7-aza-spiro[3.4]octan-6-one

The title compound was obtained as a light yellow solid, MS: m/e=305.2 (M+H⁺), using procedures similar to those described in Example 1 starting from 2-fluoro-5-bromopyridine, 1-aminomethyl-cyclobutanol (WO2006/29115 A2) and phenylacetylene.

Example 11 3-(5-Phenylethynyl-pyridin-2-yl)-1-oxa-3-aza-spiro[4.4]nonan-2-one

The title compound was obtained as a light yellow solid, MS: m/e=319.2 (M+H⁺), using procedures similar to those described in Example 1 starting from 2-fluoro-5-bromopyridine, 1-aminomethyl-cyclopentanol and phenylacetylene.

Example 12 3-(5-Phenylethynyl-pyridin-2-yl)-1-oxa-3-aza-spiro[4.5]decan-2-one

The title compound was obtained as a light yellow solid, MS: m/e=333.2 (M+H⁺), using procedures similar to those described in Example 1 starting from 2-fluoro-6-bromopyridine, 1-aminomethyl-cyclohexanol and phenylacetylene.

Example 13 4,4-Dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one

Step 1: 1-(5-Iodo-pyridin-2-yl)-3,3-dimethyl-pyrrolidine-2,5-dione

5-iodopyridin-2-amine (1 g, 4.55 mmol) was dissolved in DMF (5 ml) and 3,3-dimethyldihydrofuran-2,5-dione (1.28 g, 10.0 mmol, 2.2 equiv.) was added at room temperature. The mixture was stirred for 3 hr at 150° C. The reaction mixture was evaporated to dryness and loaded directly to a silica gel column. The crude material was purified by flash chromatography on silica gel (20 gr, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired 1-(5-iodopyridin-2-yl)-3,3-dimethylpyrrolidine-2,5-dione (1.3 g, 3.94 mmol, 86.6% yield) was obtained as a yellow solid, MS: m/e=331.0 (M+H⁺).

Step 2: (5RS)-5-Hydroxy-1-(5-iodo-pyridin-2-yl)-4,4-dimethyl-pyrrolidin-2-one

(800 mg, 2.42 mmol) 1-(5-Iodopyridin-2-yl)-3,3-dimethylpyrrolidine-2,5-dione (Example 13, step 1) was dissolved in THF (6 ml) and MeOH (2 ml) and the solution was cooled to 0-5° C. NaBH₄ (101 mg, 2.67 mmol, 1.1 equiv.) was added at 0-5° C. and the mixture was stirred for 1 hr at 0-5° C. The reaction mixture was extracted with sat. NaHCO₃ solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a amino-silica gel column and eluting with a ethyl acetate/heptane gradient, 0:100 to 100:0. The desired (5-RS)-5-hydroxy-1-(5-iodo-pyridin-2-yl)-4,4-dimethyl-pyrrolidin-2-one (370 mg, 46% yield) was obtained as a white solid, MS: m/e=333.0 (M+H⁺).

Step 3: 1-(5-Iodo-pyridin-2-yl)-4,4-dimethyl-pyrrolidin-2-one

(275 mg, 828 μmol) (5RS)-5-Hydroxy-1-(5-iodopyridin-2-yl)-4,4-dimethylpyrrolidin-2-one (Example 13, step 2) was dissolved in CH₂Cl₂ (2 ml) and trifluoroacetic anhydride (140 μl, 994 μmol, 1.2 equiv.) was added at room temperature. The mixture was stirred for 1 hr at 20-25° C. The solution was evaporated to dryness and the residue was dissolved in trifluoroacetic acid (957 μl, 12.4 mmol, 15 equiv.) and triethylsilane (159 μl, 994 μmol, 1.2 equiv.) was added at room temperature. The mixture was stirred 1 h at room temperature. The reaction mixture was evaporated and extracted with sat. NaHCO₃ solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column (20 gr, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired 1-(5-iodopyridin-2-yl)-4,4-dimethylpyrrolidin-2-one (209 mg, 80% yield) was obtained as a white solid, MS: m/e=317.0 (M+H⁺).

Step 4: 4,4-Dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one

The title compound was obtained as a yellow oil, MS: m/e=291.1 (M+H⁺), using chemistry that is described in Example 1, step 3 from 1-(5-iodo-pyridin-2-yl)-4,4-dimethyl-pyrrolidin-2-one (Example 13, step 3) and phenylacetylene.

Example 14 (3RS)-3-Hydroxy-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one

Step 1: (4RS)-4-Hydroxy-3,3-dimethyl-dihydro-furan-2,5-dione

(3RS)-3-Hydroxy-2,2-dimethyl-succinic acid [Tetrahedron Letters (2002), 43(52), 9513-9515] (120 mg, 0.74 mmol) was suspended in CH₂Cl₂ (2 ml) and cooled to 0-5° C. Trifluoroacetic anhydride (260 μl, 1.85 mmol) was added and the reaction mixture stirred for 2 hours at room temperature. The reaction mixture was evaporated to dryness and used without any further purification in the next step.

Step 2: (4RS)-4-Hydroxy-1-(5-iodo-pyridin-2-yl)-3,3-dimethyl-pyrrolidine-2,5-dione

The title compound was obtained as a light yellow solid, MS: m/e=346.8 (M+H⁺), using chemistry similar to that described in Example 12, step 1 from 5-iodopyridin-2-amine and (4RS)-4-hydroxy-3,3-dimethyl-dihydro-furan-2,5-dione (Example 14, step 1).

Step 3: (4RS)-4-(tert-Butyl-diphenyl-silanyloxy)-1-(5-iodo-pyridin-2-yl)-3,3-dimethyl-pyrrolidine-2,5-dione

(2.4 g, 3.47 mmol, 50%) (4RS)-4-Hydroxy-1-(5-iodo-pyridin-2-yl)-3,3-dimethyl-pyrrolidine-2,5-dione (Example 14, step 2) was dissolved in dichloromethane (20 ml). Imidazole (520 mg, 7.63 mmol) and tert-butyldiphenylchlorosilane (1.0 g, 3.64 mmol) were added at room temperature and the mixture was stirred for 3 hours at room temperature. Sat. NaHCO₃ solution was added and the mixture was extracted with dichloromethane. The organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (ethyl acetate/heptane gradient 0:100 to 30:70). The desired compound was obtained as a white solid (1.5 g, 74% yield), MS: m/e=585.1 (M+H⁺).

Step 4: (3RS,5RS)-3-(tert-Butyl-diphenyl-silanyloxy)-5-hydroxy-1-(5-iodo-pyridin-2-yl)-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=587.0 (M+H⁺), using chemistry similar to that described in Example 12, step 2 from (4RS)-4-(tert-butyl-diphenyl-silanyloxy)-1-(5-iodo-pyridin-2-yl)-3,3-dimethyl-pyrrolidine-2,5-dione (Example 14, step 3).

Step 5: (3RS)-3-(tert-Butyl-diphenyl-silanyloxy)-1-(5-iodo-pyridin-2-yl)-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a colorless oil, MS: m/e=571.1 (M+H⁺), using chemistry similar to that described in Example 12, step 3 from (3RS,5RS)-3-(tert-butyl-diphenyl-silanyloxy)-5-hydroxy-1-(5-iodo-pyridin-2-yl)-4,4-dimethyl-pyrrolidin-2-one (Example 14, step 4).

Step 6: (3RS)-3-(tert-Butyl-diphenyl-silanyloxy)-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one

The title compound was obtained as a brown oil, MS: m/e=545.3 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from (3RS)-3-(tert-butyl-diphenyl-silanyloxy)-1-(5-iodo-pyridin-2-yl)-4,4-dimethyl-pyrrolidin-2-one (Example 14, step 5) and phenylacetylene.

Step 7: (3RS)-3-Hydroxy-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one

(100 mg, 0.18 mmol) (3RS)-3-(tert-Butyl-diphenyl-silanyloxy)-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one (Example 14, step 6) was dissolved in THF (1 ml) and TBAF (1M in THF) (184 μl, 0.184) was added drop wise at room temperature. The mixture was stirred for 1 hr at 60° C. The reaction mixture was extracted with sat. NaHCO₃-solution and two times EtOAc. The organic layers were extracted with water, dried over Na₂SO₄, filtered and evaporated to dryness. The crude material was purified by flash chromatography on silica gel (20 gr, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired (3RS)-3-hydroxy-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one (44 mg, 78% yield) was obtained as a white solid, MS: m/e=307.3 (M+H⁺).

Example 15 4,4-Dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one

Step 1: N-1-(5-Iodo-pyridin-2-yl)-2-methyl-propane-1,2-diamine

The title compound was obtained as a colorless oil, MS: m/e=292.0 (M+H⁺), using chemistry similar to that described in Example 1, step 1 from 2-fluoro-5-iodopyridine and 2-methylpropane-1,2-diamine.

Step 2: 1-(5-Iodo-pyridin-2-yl)-4,4-dimethyl-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=318.0 (M+H⁺), using chemistry similar to that described in Example 1, step 2 from N-1-(5-iodo-pyridin-2-yl)-2-methyl-propane-1,2-diamine (Example 15, step 1).

Step 3: 4,4-Dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one

The title compound was obtained as a yellow solid, MS: m/e=292.1 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from 1-(5-iodo-pyridin-2-yl)-4,4-dimethyl-imidazolidin-2-one (Example 15, step 2) and phenylacetylene.

Example 16 3,4,4-Trimethyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one

(110 mg, 378 μmol) 4,4-Dimethyl-1-(5-(phenylethynyl)pyridin-2-yl)imidazolidin-2-one (Example 15, step 3) was dissolved in DMF (0.5 ml) and cooled to 0-5° C. NaH (55%) (19.8 mg, 453 μmol, 1.2 equiv.) was added and the mixture was stirred for 30 min at 0-5° C. Iodomethane (35.3 μl, 566 μmol, 1.5 equiv.) was added and the mixture was stirred for 30 min at 0-5° C. The reaction mixture was treated with sat. NaHCO₃ solution and extracted twice with a small volume of CH₂Cl₂. The organic layers were loaded directly to silica gel column and the crude material was purified by flash chromatography on silica gel (20 gr, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired 3,4,4-trimethyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one (93 mg, 81% yield) was obtained as a yellow solid, MS: m/e=306.2 (M+H⁺).

Example 17 3-Ethyl-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one

The title compound was obtained as a yellow oil, MS: m/e=320.2 (M+H⁺), using chemistry similar to that described in Example 16 starting from 4,4-dimethyl-1-(5-(phenylethynyl)pyridin-2-yl)imidazolidin-2-one (Example 15, step 3) and iodoethane.

Example 18 3-Isopropyl-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one

The title compound was obtained as a yellow oil, MS: m/e=334.3 (M+H⁺), using chemistry similar to that described in Example 16 starting from 4,4-dimethyl-1-(5-(phenylethynyl)pyridin-2-yl)imidazolidin-2-one (Example 15, step 3) and 2-bromopropane.

Example 19 (5RS)-5-tert-Butyl-5-methyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one

Step 1: 1-Dibenzylamino-3,3-dimethyl-butan-2-one

(2.15 ml, 16.8 mmol) Dibenzylamine was dissolved in acetonitrile (30 ml). Potassium carbonate (2.3 g, 16.8 mmol, 1.5 equiv.) and 1-bromo-3,3-dimethylbutan-2-one (1.5 ml, 11.2 mmol, 1.0 equiv.) were added and the mixture was stirred for 16 hours at 90° C. The reaction mixture was extracted with sat. NaHCO₃-solution and two times EtOAc. The organic layers were extracted with water, dried over Na₂SO₄, filtered and evaporated to dryness. The crude material was purified by flash chromatography on silica gel (70 gr, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired 1-(dibenzylamino)-3,3-dimethylbutan-2-one (1.6 g, 48.5% yield) was obtained as a yellow oil, MS: m/e=296.3 (M+H⁺).

Step 2: (RS)-1-Dibenzylamino-2,3,3-trimethyl-butan-2-ol

(1.6 g, 5.4 mmol) 1-Dibenzylamino-3,3-dimethyl-butan-2-one (Example 19, step 1) was dissolved in diethylether (20 ml) and cooled to 0-5° C. Methylmagnesium bromide (3M in diethylether) (2.2 ml, 6.5 mmol, 1.2 equiv.) was added drop wise at 0-5° C. and the mixture was stirred for 72 hours at room temperature. The reaction mixture was extracted with sat. NH₄Cl-solution and two times EtOAc. The organic layers were extracted with water, dried over Na₂SO₄, filtered and evaporated to dryness. The crude material was purified by flash chromatography on silica gel (50 gr, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired (RS)-1-dibenzylamino-2,3,3-trimethyl-butan-2-ol (1.2 g, 71% yield) was obtained as a yellow oil, MS: m/e=312.4 (M+H⁺).

Step 3: (RS)-1-Amino-2,3,3-trimethyl-butan-2-ol

The title compound was obtained as a white solid, MS: m/e=132.1 (M+H⁺), was prepared from (RS)-1-dibenzylamino-2,3,3-trimethyl-butan-2-ol (Example 19, step 2) by hydrogenation 16 hours at room temperature using Pd/C (10%) in ethyl acetate.

Step 4: (RS)-1-(5-Iodo-pyridin-2-ylamino)-2,3,3-trimethyl-butan-2-ol

The title compound was obtained as a yellow solid, MS: m/e=335.1 (M+H⁺), using chemistry similar to that described in Example 1, step 1 from 2-fluoro-5-iodopyridine and (RS)-1-amino-2,3,3-trimethyl-butan-2-ol (Example 19, step 3).

Step 5: (5RS)-5-tert-Butyl-3-(5-iodo-pyridin-2-yl)-5-methyl-oxazolidin-2-one

The title compound was obtained as a yellow oil, MS: m/e=361.1 (M+H⁺), using chemistry similar to that described in Example 1, step 2 from (RS)-1-(5-iodo-pyridin-2-ylamino)-2,3,3-trimethyl-butan-2-ol (Example 19, step 4).

Step 6: (5RS)-5-tert-Butyl-5-methyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one

The title compound was obtained as a light brown solid, MS: m/e=335.2 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from (5RS)-5-tert-butyl-3-(5-iodo-pyridin-2-yl)-5-methyl-oxazolidin-2-one (Example 19, step 5) and phenylacetylene.

Example 20 5,5-Dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

Step 1: 3-(5-Iodo-pyridin-2-yl)-5,5-dimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a colorless oil, MS: m/e=333.1 (M+H⁺), using procedures similar to those described in Example 1, step 1 and step 2 from 2-fluoro-5-iodopyridine and 3-amino-2,2-dimethylpropan-1-ol.

Step 2: 5,5-Dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

The title compound was obtained as a light brown oil, MS: m/e=307.3 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from 3-(5-iodo-pyridin-2-yl)-5,5-dimethyl-[1,3]oxazinan-2-one (Example 20, step 1) and phenylacetylene.

Example 21 1-(3-Fluoro-5-phenylethynyl-pyridin-2-yl)-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a orange solid, MS: m/e=309.2 (M+H⁺), using procedures similar to those described in Example 13 by using 2-amino-3-fluoro-5-iodopyridine instead of 5-iodopyridin-2-amine.

Example 22 (3aRS,6aSR)-3-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-cyclopentaoxazol-2-one

Step 1: (3aRS,6aSR)-3-(5-Iodo-pyridin-2-yl)-hexahydro-cyclopentaoxazol-2-one

The title compound was obtained as a light brown solid, MS: m/e=331.1 (M+H⁺), using procedures similar to those described in Example 1, step 1 and step 2 from 2-fluoro-5-iodopyridine and (1SR,2RS)-2-aminocyclopentanol hydrochloride.

Step 2: (3aRS,6aSR)-3-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-cyclopentaoxazol-2-one

The title compound was obtained as a light yellow solid, MS: m/e=305.2 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from (3aRS,6aSR)-3-(5-iodo-pyridin-2-yl)-hexahydro-cyclopentaoxazol-2-one (Example 13, step 1) and phenylacetylene.

Example 23 (3aRS,6aSR)-3-(5-Pyridin-3-ylethynyl-pyridin-2-yl)-hexahydro-cyclopentaoxazol-2-one

The title compound was obtained as a colorless oil, MS: m/e=306.2 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from (3aRS,6aSR)-3-(5-iodo-pyridin-2-yl)-hexahydro-cyclopentaoxazol-2-one (Example 13, step 1) and 3-ethynyl-pyridine.

Example 24 (3aRS,6aSR)-3-[5-(5-Fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-hexahydro-cyclopentaoxazol-2-one

The title compound was obtained as a light brown solid, MS: m/e=324.2 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from (3aRS,6aSR)-3-(5-iodo-pyridin-2-yl)-hexahydro-cyclopentaoxazol-2-one (Example 13, step 1) and 3-ethynyl-5-fluoro-pyridine (CAS 872122-54-8).

Example 25 5,5-Dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-tetrahydro-pyrimidin-2-one

The title compound was obtained as a light brown solid, MS: m/e=306.2 (M+H⁺), using procedures similar to those described in Example 15 starting from 2-fluoro-5-iodopyridine and by using 2,2-dimethylpropane-1,3-diamine instead of 2-methylpropane-1,2-diamine.

Example 26 1,5,5-Trimethyl-3-(5-phenylethynyl-pyridin-2-yl)-tetrahydro-pyrimidin-2-one

The title compound was obtained as a light brown solid, MS: m/e=306.2 (M+H⁺), using procedures similar to those described in Example 16 from 5,5-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-tetrahydro-pyrimidin-2-one (Example 25) and iodomethane.

Example 27 (RS)-4,5,5-Trimethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one

The title compound was obtained as a yellow solid, MS: m/e=307.2 (M+H⁺), using procedures similar to those described in Example 1 from 2-fluoro-5-iodopyridine and by using (RS)-3-amino-2-methyl-butan-2-ol (CAS 6291-17-4) instead of 1-amino-2-methylpropan-2-ol.

Example 28 4,4,5,5-Tetramethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=321.2 (M+H⁺), using procedures similar to those described in Example 1 from 2-fluoro-5-iodopyridine and by using 3-amino-2,3-dimethyl-butan-2-ol (CAS 89585-13-7) instead of 1-amino-2-methylpropan-2-ol.

Example 29 3-[5-(5-Fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one

Step 1: 5,5-Dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-oxazolidin-2-one

The title compound was obtained as a brown solid, MS: m/e=289.0 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from 3-(5-iodo-pyridin-2-yl)-5,5-dimethyl-oxazolidin-2-one (Example 5, step 1) and ethynyltrimethylsilane.

Step 2: 3-[5-(5-Fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one

5,5-Dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-oxazolidin-2-one (Example 29, step 1) (100 mg, 0.35 mmol) was dissolved in THF (3 ml). 3-Fluoro-5-iodopyridine (100 mg, 0.45 mmol, 1.3 equiv.), Et₃N (145 μl, 1.04 mmol, 3 equiv.), Bis-(triphenylphosphine)-palladium(II)dichloride (10 mg, 14 μmol, 0.05 equiv.), triphenylphosphine (11 mg, 17 μmol, 0.05 equiv.), triphenylphosphine (3 mg, 10 μmol, 0.03 equiv.) and copper(I)iodide (1 mg, 3.5 mmol, 0.01 equiv.) were added under nitrogen and the mixture was heated to 60° C. TBAF 1M in THF (520 μl, 0.52 mmol, 1.5 equiv.) was added dropwise in 20 minutes at 60° C. The reaction mixture was stirred for 3 hours at 60° C. Sat. NaHCO₃ solution was added and the mixture was extracted with dichloromethane. The organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (dichloromethane/methanol gradient 100:0 to 90:10). The desired 3-[5-(5-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one was obtained as a white solid (55 mg, 51% yield), MS: m/e=312.3 (M+H⁺).

Example 30 5,5-Dimethyl-3-(5-pyrimidin-5-ylethynyl-pyridin-2-yl)-oxazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=295.2 (M+H⁺), using chemistry similar to that described in Example 29, step 2 from 5,5-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-oxazolidin-2-one (Example 29, step 1) and 5-bromopyrimidine.

Example 31 5,5-Dimethyl-3-[5-(1-methyl-1H-pyrazol-4-ylethynyl)-pyridin-2-yl]-oxazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=297.2 (M+H⁺), using chemistry similar to that described in Example 29, step 2 from 5,5-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-oxazolidin-2-one (Example 29, step 1) and 4-iodo-1-methyl-1H-pyrazole.

Example 32

3-[5-(4-Fluoro-phenylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one

The title compound was obtained as a yellow solid, MS: m/e=311.2 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from 3-(5-iodo-pyridin-2-yl)-5,5-dimethyl-oxazolidin-2-one (Example 5, step 1) and 1-ethynyl-4-fluoro-benzene.

Example 33 3-[5-(3,4-Difluoro-phenylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one

The title compound was obtained as a white solid, MS: m/e=329.2 (M+H⁺), using chemistry similar to that described in Example 29, step 2 from 5,5-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-oxazolidin-2-one (Example 29, step 1) and 1,2-difluoro-4-iodobenzene.

Example 34 3-[5-(2,5-Difluoro-phenylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one

The title compound was obtained as a white solid, MS: m/e=329.2 (M+H⁺), using chemistry similar to that described in Example 29, step 2 from 5,5-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-oxazolidin-2-one (Example 29, step 1) and 1,4-difluoro-2-iodobenzene.

Example 35 3-[5-(6-Fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-5,5-dimethyl-oxazolidin-2-one

The title compound was obtained as a white solid, MS: m/e=312.2 (M+H⁺), using chemistry similar to that described in Example 29, step 2 from 5,5-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-oxazolidin-2-one (Example 29, step 1) and 2-fluoro-5-iodopyridine.

Example 36 6-(5-Pyridin-3-ylethynyl-pyridin-2-yl)-4-oxa-6-aza-spiro[2.4]heptan-5-one

The title compound was obtained as a white solid, MS: m/e=292.2 (M+H⁺), using procedures similar to those described in Example 1 starting from 2-fluoro-5-bromopyridine, 1-aminomethyl-cyclopropanol (Russian J. Org. Chem. 2001, 37, 1238) and 3-ethynyl-pyridine.

Example 37 1-[5-(5-Fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-one

Step 1: 2-Bromo-5-trimethylsilanylethynyl-pyridine

2-Bromo-5-iodopyridine (2.5 g, 8.8 mmol) was dissolved under nitrogen in 50 ml THF. Bis-(triphenylphosphine)-palladium(II)dichloride (618 mg, 880 μmol, 0.1 equiv.), ethynyltrimethylsilane (950 mg, 1.34 ml, 9.6 mmol, 1.1 equiv.), triethylamine (1.78 g, 2.44 ml, 17.6 mmol, 3 equiv.) and copper(I)iodide (84 mg, 440 μmol, 0.05 equiv.) were added and the mixture was stirred for 3 hours at 50° C. The reaction mixture was cooled and evaporated to dryness. The crude product was purified by flash chromatography on silica gel, eluting with an ethyl acetate:heptane gradient 0:100 to 15:85. The desired 2-bromo-5-trimethylsilanylethynyl-pyridine (1.95 g, 7.7 mmol, 87% yield) was obtained as a white solid, MS: m/e=254.1/256.1 (M+H⁺).

Step 2: 4,4-Dimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-2-one

(260 mg, 1.0 mmol) 2-Bromo-5-trimethylsilanylethynyl-pyridine (Example 37, step 1) was dissolved in toluene (2 ml) and 4,4-dimethylpyrrolidin-2-one (115 mg, 1.0 mmol, 1.0 equiv.), cesium carbonate (660 mg, 2.05 mmol, 2.0 equiv.), xantphos (CAS 161265-03-8) (24 mg, 0.04 mmol, 0.04 equiv.) and Pd₂(dba)₃ (19 mg, 0.02 mmol, 0.02 equiv.) were added under nitrogen. The mixture was stirred for 1 hour at 90° C. The crude product was purified by flash chromatography by directly loading the toluene mixture onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 40:60. The desired 4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-2-one (230 mg, 0.81 mmol, 75% yield) was obtained as a yellow solid, MS: m/e=287.1 (M+H⁺).

Step 3: 1-[5-(5-Fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-one

4,4-Dimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-2-one (Example 37, step 2) (80 mg, 0.28 mmol) was dissolved in DMF (1 ml). 3-Fluoro-5-iodopyridine (87 mg, 0.39 mmol, 1.4 equiv.), Et₃N (85 mg, 117 μl, 0.84 mmol, 3 equiv.), Bis-(triphenylphosphine)-palladium(II)dichloride (10 mg, 14 μmol, 0.05 equiv.), triphenylphosphine (2 mg, 8.4 μmol, 0.03 equiv.) and copper(I)iodide (2 mg, 8.4 μmol, 0.03 equiv.) were added under nitrogen and the mixture was heated to 70° C. TBAF 1M in THF (300 μl, 0.3 mmol, 1.1 equiv.) was added dropwise in 20 minutes at 70° C. The reaction mixture was stirred for 30 minutes at 70° C. and evaporated with isolute to dryness. The crude product was purified by flash chromatography with a 20 g silica gel column and eluting with heptane:ethyl acetate 100:0->0:100. The desired 1-[5-(5-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-one (36 mg, 42% yield) was obtained as a white solid, MS: m/e=310.2 (M+H⁺).

Example 38 4,4-Dimethyl-1-(5-pyridin-3-ylethynyl-pyridin-2-yl)-pyrrolidin-2-one

The title compound was obtained as a white solid, MS: m/e=292.1 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-2-one (Example 37, step 2) and 3-iodopyridine.

Example 39 1-[5-(5-Chloro-pyridin-3-ylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a white solid, MS: m/e=326.2/328.2 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-2-one (Example 37, step 2) and 3-chloro-5-iodopyridine.

Example 40 1-[5-(3-Fluoro-phenylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a white solid, MS: m/e=309.2 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-2-one (Example 37, step 2) and 1-fluoro-3-iodobenzene.

Example 41 4,4-Dimethyl-1-(3-methyl-5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one

Step 1: 2-Bromo-3-methyl-5-trimethylsilanylethynyl-pyridine

The title compound was obtained as a yellow oil, MS: m/e=268.1/270.1 (M+H⁺), using chemistry similar to that described in Example 37, step 1 by using 2-bromo-5-iodo-3-methylpyridine instead of 2-bromo-5-iodopyridine.

Step 2: 4,4-Dimethyl-1-(3-methyl-5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-2-one

The title compound was obtained as a brown solid, MS: m/e=301.3 (M+H⁺), using chemistry similar to that described in Example 37, step 2 from 2-bromo-3-methyl-5-trimethylsilanylethynyl-pyridine (Example 41, step 1) and 4,4-dimethylpyrrolidin-2-one.

Step 3: 4,4-Dimethyl-1-(3-methyl-5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one

The title compound was obtained as a white solid, MS: m/e=305.3 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 4,4-dimethyl-1-(3-methyl-5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-2-one (Example 41, step 2) and iodobenzene.

Example 42 5,5-Dimethyl-5′-phenylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one

Step 1: 5,5-Dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one

The title compound was obtained as a yellow solid, MS: m/e=301.3 (M+H⁺), using chemistry similar to that described in Example 37, step 2 from 2-bromo-5-trimethylsilanylethynyl-pyridine (Example 37, step 1) and by using 5,5-dimethyl-piperidin-2-one (CAS 4007-79-8) instead of 4,4-dimethylpyrrolidin-2-one.

Step 2: 5,5-Dimethyl-5′-phenylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one

The title compound was obtained as a yellow oil, MS: m/e=305.2 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 5,5-dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one (Example 42, step 1) and iodobenzene.

Example 43 5′-(3-Fluoro-phenylethynyl)-5,5-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one

The title compound was obtained as a yellow oil, MS: m/e=323.2 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 5,5-dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one (Example 42, step 1) and 1-fluoro-3-iodobenzene.

Example 44 1-Methyl-3-(5-phenylethynyl-pyridin-2-yl)-1,3-diaza-spiro[4.4]nonan-2-one

Step 1: {1-[(5-Iodo-pyridin-2-ylamino)-methyl]-cyclopentyl}-carbamic acid tert-butyl ester

The title compound was obtained as a white solid, MS: m/e=418.2 (M+H⁺), using chemistry similar to that described in Example 1, step 1 from 2-fluoro-5-iodopyridine and tert-1-butyl 1-(aminomethyl)cyclopentylcarbamate (CAS 889949-09-1) by using neat pyridine as solvent instead of NMP.

Step 2: (1-Amino-cyclopentylmethyl)-(5-iodo-pyridin-2-yl)-amine hydrochloride

The BOC protecting group is removed by reacting {1-[(5-iodo-pyridin-2-ylamino)-methyl]-cyclopentyl}-carbamic acid tert-butyl ester (Example 44, step 1) with 4N HCl in dioxane for 1 hour at room temperature. The title compound was obtained by filtration of the hydrochloride salt as a light yellow solid, MS: m/e=318.1 (M+H⁺).

Step 3: 3-(5-Iodo-pyridin-2-yl)-1,3-diaza-spiro[4.4]nonan-2-one

The title compound was obtained as a white solid, MS: m/e=344.1 (M+H⁺), using chemistry similar to that described in Example 1, step 2 from (1-amino-cyclopentylmethyl)-(5-iodo-pyridin-2-yl)-amine hydrochloride (Example 44, step 2).

Step 4: 3-(5-Phenylethynyl-pyridin-2-yl)-1,3-diaza-spiro[4,4]nonan-2-one

The title compound was obtained as a light yellow solid, MS: m/e=318.2 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from 3-(5-iodo-pyridin-2-yl)-1,3-diaza-spiro[4.4]nonan-2-one (Example 44, step 3) and phenylacetylene.

Step 5: 1-Methyl-3-(5-phenylethynyl-pyridin-2-yl)-1,3-diaza-spiro[4.4]nonan-2-one

The title compound was obtained as a light yellow oil, MS: m/e=332.2 (M+H⁺), using chemistry similar to that described in Example 16 from 3-(5-phenylethynyl-pyridin-2-yl)-1,3-diaza-spiro[4.4]nonan-2-one (Example 44, step 4) and iodomethane.

Example 45 (RS)-4-Cyclopentyl-3-methyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=346.2 (M+H⁺), using procedures similar to those described in Example 44 from 2-fluoro-5-iodopyridine and by using (RS)-tert-butyl 2-amino-1-cyclopentylethylcarbamate (CAS 936497-76-6) instead of tert-butyl 1-(aminomethyl)cyclopentylcarbamate.

Example 46 (1RS,5SR)-6-(5-Phenylethynyl-pyridin-2-yl)-6-aza-bicyclo[3.2.0]heptan-7-one

Step 1: (1RS,5SR)-6-(5-Bromo-pyridin-2-yl)-6-aza-bicyclo[3.2.0]heptan-7-one

The title compound was obtained as a white solid, MS: m/e=268.2 (M+H⁺), using chemistry similar to that described in Example 37, step 2 from 2,5-dibromopyridine and (1RS,5SR)-6-aza-bicyclo[3.2.0]heptan-7-one (CAS 22031-52-3).

Step 2: (1RS,5SR)-6-(5-Phenylethynyl-pyridin-2-yl)-6-aza-bicyclo[3.2.0]heptan-7-one

The title compound was obtained as a brown solid, MS: m/e=289.2 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from (1RS,5SR)-6-(5-bromo-pyridin-2-yl)-6-aza-bicyclo[3.2.0]heptan-7-one (Example 46, step 1) with phenylacetylene.

Example 47 (6SR,7RS)-3-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-benzooxazol-2-one

The title compound was obtained as a yellow solid, MS: m/e=319.2 (M+H⁺), using procedures similar to those described in Example 1 starting from 2-fluoro-5-bromopyridine, (5SR,6RS)-2-amino-cyclohexanol hydrochloride (CAS 190792-72-4) and phenylacetylene.

Example 48 3,4,4-Trimethyl-1-(5-pyridin-3-ylethynyl-pyridin-2-yl)-imidazolidin-2-one

Step 1: 1-(5-Iodo-pyridin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=332.1 (M+H⁺), using chemistry similar to that described in Example 16 from 1-(5-iodo-pyridin-2-yl)-4,4-dimethyl-imidazolidin-2-one (Example 15, step 2) and iodomethane.

Step 2: 3,4,4-Trimethyl-1-(5-pyridin-3-ylethynyl-pyridin-2-yl)-imidazolidin-2-one

The title compound was obtained as a white solid, MS: m/e=307.3 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from 1-(5-iodo-pyridin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example 48, step 1) and 3-ethynyl-pyridine.

Example 49 1-[5-(5-Fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

Step 1: 3,4,4-Trimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-imidazolidin-2-one

The title compound was obtained as a yellow solid, MS: m/e=302.3 (M+H⁺), using chemistry similar to that described in Example 37, step 1 from 1-(5-iodo-pyridin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example 48, step 1) and ethynyltrimethylsilane.

Step 2: 1-[5-(5-Fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=325.4 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 3,4,4-trimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-imidazolidin-2-one (Example 49, step 1) and 3-fluoro-5-iodopyridine.

Example 50 3,4,4-Trimethyl-1-[5-(1-methyl-1H-pyrazol-4-ylethynyl)-pyridin-2-yl]-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=310.3 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 3,4,4-trimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-imidazolidin-2-one (Example 49, step 1) and 4-iodo-1-methyl-1H-pyrazole.

Example 51 1-[5-(5-Chloro-pyridin-3-ylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

The title compound was obtained as a white solid, MS: m/e=341.1/343.3 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 3,4,4-trimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-imidazolidin-2-one (Example 49, step 1) and 3-chloro-5-iodopyridine.

Example 52 3,4,4-Trimethyl-1-(5-pyridazin-4-ylethynyl-pyridin-2-yl)-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=308.4 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 3,4,4-trimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-imidazolidin-2-one (Example 49, step 1) and 4-bromo-pyridazine.

Example 53 1-[5-(3-Fluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

The title compound was obtained as a yellow solid, MS: m/e=324.3 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from 1-(5-iodo-pyridin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example 48, step 1) and 1-ethynyl-3-fluoro-benzene.

Example 54 1-[5-(3-Chloro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

The title compound was obtained as a yellow solid, MS: m/e=340.1/342.2 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from 1-(5-iodo-pyridin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example 48, step 1) and 1-ethynyl-3-chloro-benzene.

Example 55 3,4,4-Trimethyl-1-(5-pyrimidin-5-ylethynyl-pyridin-2-yl)-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=308.2 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 3,4,4-trimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-imidazolidin-2-one (Example 49, step 1) and 5-bromo-pyrimidine.

Example 56 3,4,4-Trimethyl-1-(5-m-tolylethynyl-pyridin-2-yl)-imidazolidin-2-one

The title compound was obtained as a brown oil, MS: m/e=320.1 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from 1-(5-iodo-pyridin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example 48, step 1) and 1-ethynyl-3-methyl-benzene.

Example 57 1-[5-(4-Fluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

The title compound was obtained as a light brown solid, MS: m/e=324.2 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from 1-(5-iodo-pyridin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example 48, step 1) and 1-ethynyl-4-fluoro-benzene.

Example 58 (RS)-2-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-imidazo[1,5-a]pyridin-3-one

Step 1: (RS)-2-(5-Iodo-pyridin-2-yl)-hexahydro-imidazo[1,5-a]pyridin-3-one

The title compound was obtained as a white solid, MS: m/e=344.0 (M+H⁺), using procedures similar to those described in Example 1, step 1 and step 2 from 2-fluoro-5-iodopyridine and (RS)-hexahydro-imidazo[1,5-a]pyridin-3-one (CAS 76561-92-7) by using neat pyridine as solvent instead of NMP.

Step 2: (RS)-2-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-imidazo[1,5-a]pyridin-3-one

The title compound was obtained as a white solid, MS: m/e=318.2 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from (RS)-2-(5-iodo-pyridin-2-yl)-hexahydro-imidazo[1,5-a]pyridin-3-one (Example 58, step 1) and phenylacetylenen.

Example 59 2-(5-Phenylethynyl-pyridin-2-yl)-2-aza-spiro[4.4]nonan-3-one

The title compound was obtained as a light yellow, MS: m/e=317.2 (M+H⁺), using chemistry similar to that described in Example 37, step 2 from 2-bromo-5-phenylethynyl-pyridine (Example 58, step 1) and 2-aza-spiro[4.4]nonan-3-one (CAS 75751-72-3).

Example 60 (RS)-3-Methoxy-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one

Step 1: (RS)-4-Iodo-N-(5-iodo-pyridin-2-yl)-2-methoxy-3,3-dimethyl-butyramide

The title compound was obtained as a white solid, MS: m/e=474.9 (M+H⁺), using chemistry similar to that described in patent WO9637466, page 17, step 2 starting from (RS)-3-methoxy-4,4-dimethyl-dihydro-furan-2-one (CAS 100101-82-4) instead of 3-t-butylcarbamoyloxy-tetrahydrofuran-2-one and by using 2-amino-5-iodopyridine instead of 2-amino-4-trifluoromethylpyridine.

Step 2: (RS)-1-(5-Iodo-pyridin-2-yl)-3-methoxy-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=347.0 (M+H⁺), using chemistry similar to that described in patent WO9637466, page 17, step 3 from (RS)-4-iodo-N-(5-iodo-pyridin-2-yl)-2-methoxy-3,3-dimethyl-butyramide (Example 60, step 1).

Step 3: (RS)-3-Methoxy-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=321.3 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from (RS)-1-(5-iodo-pyridin-2-yl)-3-methoxy-4,4-dimethyl-pyrrolidin-2-one (Example 60, step 2) and phenylacetylene.

Example 61 (5R or 5S)-5-Methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one

The title compound, a yellow oil, MS: m/e=321.3 (M+H⁺), was prepared by separation of (RS)-3-methoxy-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one (Example 60) using a chiral column (chiralpak AD with heptane:isopropanol 90:10 as solvent).

Example 62 (5S or 5R)-5-Methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one

The title compound, a white solid, MS: m/e=321.3 (M+H⁺), was prepared by separation of (RS)-3-methoxy-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one (Example 60) using a chiral column (chiralpak AD with heptane:isopropanol 90:10 as solvent).

Example 63 (RS)-1-[5-(5-Chloro-pyridin-3-ylethynyl)-pyridin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one

Step 1: (RS)-3-Methoxy-4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-2-one

The title compound was obtained as a yellow solid, MS: m/e=317.2 (M+H⁺), using chemistry similar to that described in Example 37, step 1 from (RS)-1-(5-iodo-pyridin-2-yl)-3-methoxy-4,4-dimethyl-pyrrolidin-2-one (Example 60, step 2) and ethynyltrimethylsilane.

Step 2: (RS)-1-[5-(5-Chloro-pyridin-3-ylethynyl)-pyridin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a white solid, MS: m/e=356.1/358.2 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from (RS)-3-methoxy-4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-2-one (Example 63, step 1) and 3-chloro-5-iodopyridine.

Example 64 (RS)-3-Methoxy-4,4-dimethyl-1-(5-m-tolylethynyl-pyridin-2-yl)-pyrrolidin-2-one

The title compound was obtained as an orange oil, MS: m/e=335.2 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from (RS)-1-(5-iodo-pyridin-2-yl)-3-methoxy-4,4-dimethyl-pyrrolidin-2-one (Example 60, step 2) and 1-ethynyl-3-methyl-benzene.

Example 65 (RS)-1-[5-(3-Fluoro-phenylethynyl)-pyridin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a brown solid, MS: m/e=339.2 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from (RS)-1-(5-iodo-pyridin-2-yl)-3-methoxy-4,4-dimethyl-pyrrolidin-2-one (Example 60, step 2) and 1-ethynyl-3-fluorobenzene.

Example 66 (RS)-1-[5-(4-Fluoro-phenylethynyl)-pyridin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a brown solid, MS: m/e=339.2 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from (RS)-1-(5-iodo-pyridin-2-yl)-3-methoxy-4,4-dimethyl-pyrrolidin-2-one (Example 60, step 2) and 1-ethynyl-4-fluorobenzene.

Example 67 3,4,4-Trimethyl-1-(5-phenylethynyl-pyridin-2-yl)-tetrahydro-pyrimidin-2-one

Step 1: [3-(5-Iodo-pyridin-2-ylamino)-1,1-dimethyl-propyl]-carbamic acid tert-butyl ester

The title compound was obtained as a white solid, MS: m/e=406.3 (M+H⁺), using chemistry similar to that described in Example 1, step 1 from 2-fluoro-5-iodopyridine and tert-butyl 4-amino-2-methylbutan-2-ylcarbamate (CAS 880100-43-6).

Step 2: N-1-(5-Iodo-pyridin-2-yl)-3-methyl-butane-1,3-diamine hydrochloride

The BOC protecting group is removed by reacting [3-(5-iodo-pyridin-2-ylamino)-1,1-dimethyl-propyl]-carbamic acid tert-butyl ester (Example 67, step 1) with 4N HCl in dioxane for 4 hours at room temperature. The title compound was obtained by filtration of the hydrochloride salt as a pink solid, MS: m/e=306.1 (M+H⁺).

Step 3: 1-(5-Iodo-pyridin-2-yl)-4,4-dimethyl-tetrahydro-pyrimidin-2-one

The title compound was obtained as a yellow solid, MS: m/e=332.1 (M+H⁺), using chemistry similar to that described in Example 1, step 2 from N-1-(5-iodo-pyridin-2-yl)-3-methyl-butane-1,3-diamine hydrochloride (Example 67, step 2).

Step 4: 1-(5-Iodo-pyridin-2-yl)-3,4,4-trimethyl-tetrahydro-pyrimidin-2-one

The title compound was obtained as a yellow solid, MS: m/e=346.0 (M+H⁺), using chemistry similar to that described in Example 16 from 1-(5-iodo-pyridin-2-yl)-4,4-dimethyl-tetrahydro-pyrimidin-2-one (Example 67, step 3) and iodomethane.

Step 5: 3,4,4-Trimethyl-1-(5-phenylethynyl-pyridin-2-yl)-tetrahydro-pyrimidin-2-one

The title compound was obtained as a brown solid, MS: m/e=320.2 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from 1-(5-iodo-pyridin-2-yl)-3,4,4-trimethyl-tetrahydro-pyrimidin-2-one (Example 67, step 4) and phenylacetylene.

Example 68 1-[5-(2,5-Difluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-tetrahydro-pyrimidin-2-one

Step 1: 3,4,4-Trimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-tetrahydro-pyrimidin-2-one

The title compound was obtained as a white solid, MS: m/e=316.2 (M+H⁺), using chemistry similar to that described in Example 37, step 1 from 1-(5-iodo-pyridin-2-yl)-3,4,4-trimethyl-tetrahydro-pyrimidin-2-one (Example 67, step 4) and ethynyltrimethylsilane.

Step 2: 1-[5-(2,5-Difluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-tetrahydro-pyrimidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=356.2 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 3,4,4-trimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-tetrahydro-pyrimidin-2-one (Example 68, step 1) and 1,4-difluoro-2-iodobenzene.

Example 69 1-[5-(4-Fluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-tetrahydro-pyrimidin-2-one

The title compound was obtained as a white solid, MS: m/e=338.3 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 3,4,4-trimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-tetrahydro-pyrimidin-2-one (Example 68, step 1) and 1-fluoro-4-iodobenzene.

Example 70 (RS)-2-(5-Pyridin-3-ylethynyl-pyridin-2-yl)-hexahydro-imidazo[1,5-a]pyridin-3-one

The title compound was obtained as a light yellow solid, MS: m/e=319.1 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from (RS)-2-(5-iodo-pyridin-2-yl)-hexahydro-imidazo[1,5-a]pyridin-3-one (Example 58, step 1) and 3-ethynyl-pyridine.

Example 71 (RS)-2-[5-(3-Fluoro-phenylethynyl)-pyridin-2-yl]-hexahydro-imidazo[1,5-a]pyridin-3-one

The title compound was obtained as a light brown solid, MS: m/e=336.2 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from (RS)-2-(5-iodo-pyridin-2-yl)-hexahydro-imidazo[1,5-a]pyridin-3-one (Example 58, step 1) and 1-ethynyl-3-fluorobenzene.

Example 72 6,6-Dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

Step 1: (3-Hydroxy-3-methyl-butyl)-carbamic acid benzyl ester

(10 g, 42.1 mmol) Methyl 3-(benzyloxycarbonylamino)propanoate (CAS 54755-77-0) was dissolved in THF (150 ml) and cooled to 0-5° C. 3N Methylmagnesium bromide in THF (56.2 ml, 120 mmol, 4 equiv.) was added drop wise and the mixture stirred for 1 hour at 0-5° C. The reaction mixture was extracted with saturated NH₄Cl solution and two times with EtOAc. The organic layers were dried over Na₂SO₄ and evaporated to dryness. The desired (3-hydroxy-3-methyl-butyl)-carbamic acid benzyl ester (11.6 g, quant.) was obtained as a colorless oil, MS: m/e=238.1 (M+H⁺) and used in the next step without further purification.

Step 2: 6,6-dimethyl-[1,3]oxazinan-2-one

(11.6 g, 48.9 mmol) (3-Hydroxy-3-methyl-butyl)-carbamic acid benzyl ester (Example 72, step 1) was dissolved in THF (250 ml) and sodium hydride (60%, 5.2 g, 108 mmol, 2.2 equiv.) was added in portions. The mixture was stirred for 3 hours at room temperature. 5 ml saturated NaHCO₃ solution was added carefully and the mixture was evaporated with isolute to dryness. The crude product was purified by flash chromatography by directly loading the residue onto a silica gel column and eluting with an ethyl acetate:methanol gradient 100:0 to 90:10. The desired 6,6-dimethyl-[1,3]oxazinan-2-one (3.2 g, 51% yield) was obtained as a yellow solid, MS: m/e=130.1 (M+H⁺).

Step 3: 6,6-Dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

The title compound was obtained as an orange solid, MS: m/e=303.2 (M+H⁺), using chemistry similar to that described in Example 37, step 2 from 2-bromo-5-trimethylsilanylethynyl-pyridine (Example 37, step 1) and by using 6,6-dimethyl-[1,3]oxazinan-2-one (Example 72, step 2) instead of 4,4-dimethylpyrrolidin-2-one.

Step 4: 6,6-Dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

The title compound was obtained as a yellow solid, MS: m/e=307.2 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 6,6-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one (Example 72, step 3) and iodobenzene.

Example 73 6,6-Dimethyl-3-(5-pyridin-3-ylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

Step 1: 3-(5-Iodo-pyridin-2-yl)-6,6-dimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a white solid, MS: m/e=333.1 (M+H⁺), using procedures similar to those described in Example 1, step 1 and step 2 from 2-fluoro-5-iodopyridine and 4-amino-2-methyl-butan-2-ol hydrochloride.

Step 2: 6,6-Dimethyl-3-(5-pyridin-3-ylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

The title compound was obtained as a light yellow solid, MS: m/e=308.2 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from 3-(5-iodo-pyridin-2-yl)-6,6-dimethyl-[1,3]oxazinan-2-one (Example 73, step 1) and phenylacetylene.

Example 74 3-[5-(5-Fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a white solid, MS: m/e=326.3 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 6,6-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one (Example 72, step 3) and 3-fluoro-5-iodopyridine.

Example 75 3-[5-(5-Chloro-pyridin-3-ylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a white solid, MS: m/e=342.1/344.2 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 6,6-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one (Example 72, step 3) and 3-chloro-5-iodopyridine.

Example 76 3-[5-(3-Fluoro-phenylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a white solid, MS: m/e=325.4 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 6,6-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one (Example 72, step 3) and 1-fluoro-3-iodobenzene.

Example 77 3-[5-(3-Chloro-phenylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a white solid, MS: m/e=341.2/343.2 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 6,6-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one (Example 72, step 3) and 1-chloro-3-iodobenzene.

Example 78 6,6-Dimethyl-3-(5-m-tolylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

The title compound was obtained as a light yellow solid, MS: m/e=321.4 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 6,6-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one (Example 72, step 3) and 1-iodo-3-methylbenzene.

Example 79 3-[5-(4-Fluoro-phenylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a light brown solid, MS: m/e=325.2 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from 3-(5-iodo-pyridin-2-yl)-6,6-dimethyl-[1,3]oxazinan-2-one (Example 73, step 1) and 1-ethynyl-4-fluorobenzene.

Example 80 3-[5-(3,4-Difluoro-phenylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a light yellow solid, MS: m/e=343.1 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from 3-(5-iodo-pyridin-2-yl)-6,6-dimethyl-[1,3]oxazinan-2-one (Example 73, step 1) and 4-ethynyl-1,2-difluorobenzene.

Example 81 3-[5-(2,5-Difluoro-phenylethynyl)-pyridin-2-yl]-6,6-dimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a light yellow solid, MS: m/e=343.1 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 6,6-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one (Example 72, step 3) and 1,4-difluoro-2-iodobenzene.

Example 82 6-(5-Phenylethynyl-pyridin-2-yl)-2-oxa-6-aza-spiro[3.4]octan-7-one

Step 1: 6-(5-Trimethylsilanylethynyl-pyridin-2-yl)-2-oxa-6-aza-spiro[3.4]octan-7-one

The title compound was obtained as a white solid, MS: m/e=301.3 (M+H⁺), using chemistry similar to that described in Example 37, step 2 from 2-bromo-5-trimethylsilanylethynyl-pyridine (Example 37, step 1) and 2-oxa-6-aza-spiro[3.4]octan-7-one (CAS 1207174-87-5).

Step 2: 6-(5-Phenylethynyl-pyridin-2-yl)-2-oxa-6-aza-spiro[3.4]octan-7-one

The title compound was obtained as a light yellow solid, MS: m/e=305.3 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 6-(5-trimethylsilanylethynyl-pyridin-2-yl)-2-oxa-6-aza-spiro[3.4]octan-7-one (Example 82, step 1) and iodobenzene.

Example 83 (RS)-4-Cyclopropyl-3-methyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one

The title compound was obtained as an orange solid, MS: m/e=318.1 (M+H⁺), using procedures similar to those described in Example 58 from 2-fluoro-5-iodopyridine and by using (RS)-1-cyclopropyl-ethane-1,2-diamine instead of (RS)-hexahydro-imidazo[1,5-a]pyridin-3-one.

Example 84 (3aSR,7aRS)-(3 aRS,7RS)-1-Methyl-3-(5-phenylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one

Step 1: (1SR,2RS)-(1RS,2RS)—N-(5-Iodo-pyridin-2-yl)-cyclohexane-1,2-diamine

The title compound was obtained as a brown oil, MS: m/e=318.1 (M+H⁺), using chemistry similar to that described in Example 1, step 1 from 2-fluoro-5-iodopyridine and rac-cyclohexane-1,2-diamine.

Step 2: (3aSR,7aRS)-(3aRS,7aRS)-1-(5-Iodo-pyridin-2-yl)-octahydro-benzoimidazol-2-one

The title compound was obtained as a yellow solid, MS: m/e=344.1 (M+H⁺), using chemistry similar to that described in Example 1, step 2 from (1SR,2RS)-(1RS,2RS)—N-(5-iodo-pyridin-2-yl)-cyclohexane-1,2-diamine (Example 84, step 1).

Step 3: (3aSR,7aRS)-(3aRS,7aRS)-1-(5-Iodo-pyridin-2-yl)-3-methyl-octahydro-benzoimidazol-2-one

The title compound was obtained as a white solid, MS: m/e=358.0 (M+H⁺), using chemistry similar to that described in Example 16 from (3aSR,7aRS)-(3aRS,7aRS)-1-(5-iodo-pyridin-2-yl)-octahydro-benzoimidazol-2-one (Example 84, step 2) and iodomethane.

Step 4: (3aSR,7aRS)-(3aRS,7RS)-1-Methyl-3-(5-phenylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one

The title compound was obtained as a yellow solid, MS: m/e=332.3 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from (3aSR,7aRS)-(3aRS,7aRS)-1-(5-iodo-pyridin-2-yl)-3-methyl-octahydro-benzoimidazol-2-one (Example 84, step 3) and phenylacetylene.

Example 85 (3aSR,7aRS)-(3aRS,7RS)-1-Methyl-3-(5-pyridin-3-ylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one

The title compound was obtained as a light yellow solid, MS: m/e=333.3 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from (3aSR,7aRS)-(3aRS,7aRS)-1-(5-iodo-pyridin-2-yl)-3-methyl-octahydro-benzoimidazol-2-one (Example 84, step 3) and 3-ethynylpyridine.

Example 86 (3aSR,7aRS)-(3aRS,7RS)-1-[5-(5-Fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-3-methyl-octahydro-benzoimidazol-2-one

The title compound was obtained as a light yellow solid, MS: m/e=351.3 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from (3aSR,7aRS)-(3aRS,7aRS)-1-(5-iodo-pyridin-2-yl)-3-methyl-octahydro-benzoimidazol-2-one (Example 84, step 3) and 3-ethynyl-5-fluoro-pyridine (generated by in situ Sonogashira reaction of 3-fluoro-5-iodopyridine with ethynyltrimethylsilane and TBAF).

Example 87 4,4-Dimethyl-5′-phenylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one

Step 1: 4,4-Dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one

The title compound was obtained as a yellow solid, MS: m/e=301.3 (M+H⁺), using chemistry similar to that described in Example 37, step 2 from 2-bromo-5-trimethylsilanylethynyl-pyridine (Example 37, step 1) and by using 4,4-dimethyl-piperidin-2-one (CAS 55047-81-9) instead of 4,4-dimethylpyrrolidin-2-one.

Step 2: 4,4-Dimethyl-5′-phenylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one

The title compound was obtained as a white solid, MS: m/e=305.2 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 4,4-dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one (Example 87, step 1) and iodobenzene.

Example 88 5′-(3-Fluoro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one

The title compound was obtained as a white solid, MS: m/e=323.2 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 4,4-dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one (Example 87, step 1) and 1-fluoro-3-iodobenzene.

Example 89 5′-(3-Chloro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one

The title compound was obtained as a light yellow solid, MS: m/e=339.2/341.1 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 4,4-dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one (Example 87, step 1) and 1-chloro-3-iodobenzene.

Example 90 5′-(5-Chloro-pyridin-3-ylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one

The title compound was obtained as a light yellow solid, MS: m/e=340.1/342.2 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 4,4-dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one (Example 87, step 1) and 1-chloro-3-iodopyridine.

Example 91 5′-(4-Fluoro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one

The title compound was obtained as a light yellow solid, MS: m/e=323.2 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 4,4-dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one (Example 87, step 1) and 1-fluoro-4-iodobenzene.

Example 92 5′-(2,5-Difluoro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one

The title compound was obtained as a white solid, MS: m/e=341.1 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 4,4-dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one (Example 87, step 1) and 1,4-difluoro-2-iodobenzene.

Example 93 7,7-Dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazepan-2-one

Step 1: 3-(5-Iodo-pyridin-2-yl)-7,7-dimethyl-[1,3]oxazepan-2-one

The title compound was obtained as a colorless oil, MS: m/e=346.9 (M+H⁺), using procedures similar to those described in Example 1, step 1 and step 2 from 2-fluoro-5-iodopyridine and 5-amino-2-methylpentan-2-ol (CAS 108262-66-4).

Step 2: 7,7-Dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazepan-2-one

The title compound was obtained as an orange solid, MS: m/e=321.2 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from 3-(5-iodo-pyridin-2-yl)-7,7-dimethyl-[1,3]oxazepan-2-one (Example 93, step 1) and phenylacetylene.

Example 94 (3aSR,7aRS)-(3aRS,7RS)-1-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-pyrano[4,3-d]oxazol-2-one

Step 1: (3aSR,7aRS)-(3aRS,7RS)-1-(5-Iodo-pyridin-2-yl)-hexahydro-pyrano[4,3-d]oxazol-2-one

The title compound was obtained as a white solid, MS: m/e=346.9 (M+H⁺), using procedures similar to those described in Example 1, step 1 and step 2 from 2-fluoro-5-iodopyridine and (3RS,4RS)-(3RS,4SR)-4-aminotetrahydro-2H-pyran-3-ol (CAS 33332-01-3).

Step 2: (3aSR,7aRS)-(3aRS,7RS)-1-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-pyrano[4,3-d]oxazol-2-one

The title compound was obtained as a brown solid, MS: m/e=321.1 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from (3aSR,7aRS)-(3aRS,7RS)-1-(5-iodo-pyridin-2-yl)-hexahydro-pyrano[4,3-d]oxazol-2-one (Example 94, step 1) and phenylacetylene.

Example 95 (RS)-5-Hydroxy-6,6-dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

Step 1: (RS)-2-(tert-Butyl-diphenyl-silanyloxy)-3-dibenzylamino-propionic acid ethyl ester

(5.8 g, 18.6 mmol) (RS)-3-Dibenzylamino-2-hydroxy-propionic acid ethyl ester (CAS 93715-75-4) was dissolved in DMF (40 ml) and tert-butylchlorodiphenylsilane (6.76 ml, 26 mmol, 1.4 equiv.), Imidazole (1.9 g, 27.9 mmol, 1.5 equiv.) and DMAP (227 mg, 1.9 mmol, 0.1 equiv.) were added at room temperature. The mixture was stirred for 3 hours at 80° C. The reaction mixture was evaporated and extracted with saturated NaHCO₃ solution and two times with EtOAc. The organic layers were extracted with brine, dried over Na₂SO₄ and evaporated to dryness. The crude product was purified by flash chromatography on silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 40:60. The desired (RS)-2-(tert-butyl-diphenyl-silanyloxy)-3-dibenzylamino-propionic acid ethyl ester (8.1 g, 79% yield) was obtained as a colorless oil, MS: m/e=552.5 (M+H⁺).

Step 2: (RS)-3-(tert-Butyl-diphenyl-silanyloxy)-4-dibenzylamino-2-methyl-butan-2-ol

(8.0 g, 14.5 mmol) (RS)-2-(tert-Butyl-diphenyl-silanyloxy)-3-dibenzylamino-propionic acid ethyl ester (Example 95, step 1) was dissolved in THF (100 ml) and methylmagnesium bromide (3M in diethylether) (19.3 ml, 58 mmol, 4 equiv.) was drop wise at room temperature. The mixture was stirred for 3.5 hours at room temperature. The reaction mixture was extracted with saturated NaHCO₃ solution and two times with EtOAc. The organic layers were extracted with brine, dried over Na₂SO₄ and evaporated to dryness. The desired (RS)-3-(tert-butyl-diphenyl-silanyloxy)-4-dibenzylamino-2-methyl-butan-2-ol (6.9 g, 84% yield) was obtained as a white solid, MS: m/e=538.5 (M+H⁺) and used in the next step without further purification.

Step 3: (RS)-4-Amino-3-(tert-butyl-diphenyl-silanyloxy)-2-methyl-butan-2-ol

(RS)-3-(tert-Butyl-diphenyl-silanyloxy)-4-dibenzylamino-2-methyl-butan-2-ol (Example 95, step 2) was hydrogenated in EtOH with Pd(OH)₂ for 16 hours at 60° C. The desired (RS)-4-amino-3-(tert-butyl-diphenyl-silanyloxy)-2-methyl-butan-2-ol (4.2 g, 92% yield) was obtained as a colorless oil, MS: m/e=358.2 (M+H⁺) and used in the next step without further purification.

Step 4: (RS)-5-(2,2-Dimethyl-1,1-diphenyl-propoxy)-6,6-dimethyl-[1,3]oxazinan-2-one

(1.83 mg, 5.1 mmol) (RS)-4-Amino-3-(tert-butyl-diphenyl-silanyloxy)-2-methyl-butan-2-ol (Example 95, step 3) was dissolved in THF (35 ml) and cooled to 0-5° C. Triethylamine (2.14 ml, 15.4 mmol, 3 equiv.) and triphosgene (1.67 g, 5.63 mmol, 1.1 equiv.) dissolved in 15 ml THF were added drop wise at 0-5° C. The mixture was stirred for 1 hour at 0-5° C. The reaction mixture was evaporated with isolute and the crude product was purified by flash chromatography by directly loading the residue onto a silica gel column and eluting with a heptane:ethyl acetate gradient 100:0 to 0:100. The desired (RS)-5-(2,2-dimethyl-1,1-diphenyl-propoxy)-6,6-dimethyl-[1,3]oxazinan-2-one (535 mg, 27% yield) was obtained as a white solid, MS: m/e=384.3 (M+H⁺).

Step 5: (RS)-5-(2,2-Dimethyl-1,1-diphenyl-propoxy)-6,6-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

The title compound was obtained as a yellow oil, MS: m/e=557.3 (M+H⁺), using chemistry similar to that described in Example 37, step 2 from 2-bromo-5-trimethylsilanylethynyl-pyridine (Example 37, step 1) and (RS)-5-(2,2-dimethyl-1,1-diphenyl-propoxy)-6,6-dimethyl-[1,3]oxazinan-2-one (Example 95, step 4).

Step 6: (RS)-5-Hydroxy-6,6-dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

The title compound was obtained as a light yellow solid, MS: m/e=323.1 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from (RS)-5-(2,2-dimethyl-1,1-diphenyl-propoxy)-6,6-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one (Example 95, step 5) and iodobenzene.

Example 96 4-Methyl-6-(5-phenylethynyl-pyridin-2-yl)-4,6-diaza-spiro[2.4]heptan-5-one

Step 1: 2-Bromo-5-phenylethynyl-pyridine

The title compound was obtained as a white solid, MS: m/e=258/260 (M+H⁺), using chemistry similar to that described in Example 37, step 1 from 2-bromo-5-iodopyridine and by using phenylacetylene instead of ethynyltrimethylsilane.

Step 2: 4,6-Diaza-spiro[2.4]heptan-5-one

(0.88 g, 5.53 mmol) 1-(Aminomethyl)cyclopropanamine dihydrochloride (CAS 849149-67-3) was dissolved in THF (10 ml) and CDI (0.9 g, 5.53 mmol, 1.0 equiv.) was added at room temperature. The mixture was stirred for 16 hours at 70° C. The reaction mixture was evaporated and extracted with saturated NaHCO₃ solution and five times with dichloromethane. The organic layers were dried over Na₂SO₄ and evaporated to dryness. The desired 4,6-diaza-spiro[2.4]heptan-5-one (0.52 g, 50% purity, 42% yield) was obtained as a white solid, MS: m/e=113.0 (M+H⁺) and was used without further purification in the next step.

Step 3: 6-(5-Phenylethynyl-pyridin-2-yl)-4,6-diaza-spiro[2.4]heptan-5-one

The title compound was obtained as a yellow solid, MS: m/e=290.1 (M+H⁺), using chemistry similar to that described in Example 37, step 2 from 2-bromo-5-phenylethynyl-pyridine (Example 96, step 1) and 4,6-diaza-spiro[2.4]heptan-5-one (Example 96, step 2).

Step 4: 4-Methyl-6-(5-phenylethynyl-pyridin-2-yl)-4,6-diaza-spiro[2.4]heptan-5-one

The title compound was obtained as a white solid, MS: m/e=304.1 (M+H⁺), using chemistry similar to that described in Example 16 from 6-(5-phenylethynyl-pyridin-2-yl)-4,6-diaza-spiro[2.4]heptan-5-one (Example 96, step 3) and iodomethane.

Example 97 3,3-Dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-azetidin-2-one

Step 1: N-(5-Bromo-pyridin-2-yl)-3-chloro-2,2-dimethyl-propionamide

To a solution of 2-amino-5-bromopyridine (100 mg, 0.454 mmol) in dichloromethane (6 ml) were added triethylamine (0.19 ml, 1.364 mmol, 3 equiv.) and 3-chloro-2,2-dimethyl-propionyl chloride (CAS 4300-97-4) (140 mg, 0.909 mmol, 2 equiv.) at 0-5° C. The mixture was stirred for 16 hours at room temperature. The reaction mixture was evaporated and the crude product was purified by flash chromatography on silica gel column and eluting with an ethyl acetate:heptane gradient 5:95 to 10:90. The desired N-(5-bromo-pyridin-2-yl)-3-chloro-2,2-dimethyl-propionamide (154 mg, 74% yield) was obtained as a white solid.

Step 2: 1-(5-Bromo-pyridin-2-yl)-3,3-dimethyl-azetidin-2-one

(250 mg, 0.738 mmol) N-(5-Bromo-pyridin-2-yl)-3-chloro-2,2-dimethyl-propionamide (Example 97, step 1) dissolved in DMF (3 ml) was added at room temperature to a solution of NaH (29.5 mg, 0.738 mmol, 1 equiv.) in 5 ml DMF. The mixture was stirred for 3 hours at 70° C. The reaction mixture was evaporated and the crude product was purified by flash chromatography on silica gel column and eluting with an ethyl acetate:heptane gradient 10:90 to 15:85. The desired 1-(5-bromo-pyridin-2-yl)-3,3-dimethyl-azetidin-2-one (160 mg, 72% yield) was obtained as a white solid.

Step 3: 3,3-Dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-azetidin-2-one

The title compound was obtained as a brown solid, MS: m/e=277.0 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from 1-(5-bromo-pyridin-2-yl)-3,3-dimethyl-azetidin-2-one (Example 97, step 2) and phenylacetylene.

Example 98 (1RS,5SR)-6-(5-Pyridin-3-ylethynyl-pyridin-2-yl)-6-aza-bicyclo[3.2.0]heptan-7-one

The title compound was obtained as a brown solid, MS: m/e=290.2 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from (1RS,5SR)-6-(5-bromo-pyridin-2-yl)-6-aza-bicyclo[3.2.0]heptan-7-one (Example 46, step 1) with 3-ethynyl-pyridine.

Example 99 (3aSR,7aRS)-(3aRS,7RS)-1-Ethyl-3-(5-phenylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one

Step 1: (3aSR,7aRS)-(3aRS,7aRS)-1-(5-Iodo-pyridin-2-yl)-3-ethyl-octahydro-benzoimidazol-2-one

The title compound was obtained as a light yellow solid, MS: m/e=372.2 (M+H⁺), using chemistry similar to that described in Example 16 from (3aSR,7aRS)-(3aRS,7aRS)-1-(5-iodo-pyridin-2-yl)-octahydro-benzoimidazol-2-one (Example 84, step 2) and iodoethane by stirring the reaction at 60° C. instead of 0-5° C.

Step 2: (3aSR,7aRS)-(3aRS,7RS)-1-Ethyl-3-(5-phenylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one

The title compound was obtained as a brown oil, MS: m/e=346.4 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from (3aSR,7aRS)-(3aRS,7aRS)-1-(5-iodo-pyridin-2-yl)-3-ethyl-octahydro-benzoimidazol-2-one (Example 99, step 1) and phenylacetylene.

Example 100 (3aSR,7aRS)-(3aRS,7RS)-1-Ethyl-3-(5-pyridin-3-ylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one

The title compound was obtained as a brown solid, MS: m/e=347.8 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from (3aSR,7aRS)-(3aRS,7aRS)-1-(5-iodo-pyridin-2-yl)-3-ethyl-octahydro-benzoimidazol-2-one (Example 99, step 1) and 3-ethynyl-pyridine.

Example 101 (3aSR,7aRS)-(3aRS,7RS)-1-Isopropyl-3-(5-phenylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one

Step 1: (3aSR,7aRS)-(3aRS,7aRS)-1-(5-Iodo-pyridin-2-yl)-3-isopropyl-octahydro-benzoimidazol-2-one

The title compound was obtained as a white solid using chemistry similar to that described in Example 16 from (3aSR,7aRS)-(3aRS,7aRS)-1-(5-iodo-pyridin-2-yl)-octahydro-benzoimidazol-2-one (Example 84, step 2) and isopropyl iodide by stirring the reaction at 60° C. instead of 0-5° C.

Step 2: (3aSR,7aRS)-(3aRS,7RS)-1-Isopropyl-3-(5-phenylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one

The title compound was obtained as a brown oil, MS: m/e=360.1 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from (3aSR,7aRS)-(3aRS,7aRS)-1-(5-iodo-pyridin-2-yl)-3-isopropyl-octahydro-benzoimidazol-2-one (Example 101, step 1) and phenylacetylene.

Example 102 (4aRS,7aSR)-3-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-cyclopenta[e][1,3]oxazin-2-one

Step 1: (4aRS,7aSR)-3-(5-Iodo-pyridin-2-yl)-hexahydro-cyclopenta[e][1,3]oxazin-2-one

The title compound was obtained as a white solid, MS: m/e=345.0 (M+H⁺), using procedures similar to those described in Example 1, step 1 and step 2 from 2-fluoro-5-iodopyridine and (1SR,2RS)-2-aminomethyl-cyclopentanol (CAS 40482-02-8) by using triphosgene and triethylamine in THF for 12 hours at room temperature instead of the conditions used in Example 1, step 2.

Step 2: (4aRS,7aSR)-3-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-cyclopenta[e][1,3]oxazin-2-one

The title compound was obtained as a brown solid, MS: m/e=319.0 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from (4aRS,7aSR)-3-(5-iodo-pyridin-2-yl)-hexahydro-cyclopenta[e][1,3]oxazin-2-one (Example 102, step 1) and phenylacetylene.

Example 103 (4aRS,7aRS)-3-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-cyclopenta[e][1,3]oxazin-2-one

Step 1: (4aRS,7aRS)-3-(5-Iodo-pyridin-2-yl)-hexahydro-cyclopenta[e][1,3]oxazin-2-one

The title compound was obtained as a white solid, MS: m/e=345.0 (M+H⁺), using procedures similar to those described in Example 1, step 1 and step 2 from 2-fluoro-5-iodopyridine and (1SR,2SR)-2-aminomethyl-cyclopentanol (CAS 40482-00-6) by using triphosgene and triethylamine in THF for 12 hours at room temperature instead of the conditions used in Example 1, step 2.

Step 2: (4aRS,7aRS)-3-(5-Phenylethynyl-pyridin-2-yl)-hexahydro-cyclopenta[e][1,3]oxazin-2-one

The title compound was obtained as a brown solid, MS: m/e=318.8 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from (4aRS,7aRS)-3-(5-iodo-pyridin-2-yl)-hexahydro-cyclopenta[e][1,3]oxazin-2-one (Example 103, step 1) and phenylacetylene.

Example 104 (RS)-5,6,6-Trimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

Step 1: (RS)-(3-Hydroxy-2,3-dimethyl-butyl)-carbamic acid tert-butyl ester

The title compound was obtained as a colorless oil, MS: m/e=218.3 (M+H⁺), using chemistry similar to that described in Example 95, step 2 from methyl 3-(tert-butoxycarbonylamino)-2-methylpropanoate (CAS 182486-16-4).

Step 2: (RS)-5,6,6-Trimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a yellow solid, MS: m/e=144.0 (M+H⁺), using chemistry similar to that described in Example 72, step 2 from (RS)-(3-hydroxy-2,3-dimethyl-butyl)-carbamic acid tert-butyl ester (Example 104, step 1).

Step 3: (RS)-5,6,6-Trimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

The title compound was obtained as a yellow oil, MS: m/e=321.1 (M+H⁺), using chemistry similar to that described in Example 37, step 2 from 2-bromo-5-phenylethynyl-pyridine (Example 96, step 1) and (RS)-5,6,6-trimethyl-[1,3]oxazinan-2-one (Example 104, step 2).

Example 105 (RS)-6-Methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

The title compound was obtained as a light yellow solid, MS: m/e=323.1 (M+H⁺), using chemistry similar to that described in Example 37, step 2 from 2-bromo-5-phenylethynyl-pyridine (Example 96, step 1) and (RS)-6-methoxymethyl-[1,3]oxazinan-2-one (CAS 39754-63-7).

Example 106 (3aRS, 6aSR)-1-methyl-3-(5-(phenylethynyl) pyridin-2-yl)hexahydrocyclopenta[d]imidazol-2(1H)-one

Step 1: (3aSR, 6aRS)-2-oxo-hexahydro-cyclopentaimidazole-1-carboxylic acid tert-butyl ester

A solution of (rac)-cis-2-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (2.28 g, 9.98 mmol) and N-methylmorpholine (1.1 g, 1.21 ml, 11.0 mmol, 1.1 equiv.) in 28 ml of dichloroethane was stirred at r.t. for 10 min. Then diphenylphosphoricacid azide (3.02 g, 2.37 ml, 11.0 mmol, 1.1 equiv.) was added dropwise at room temperature and the colorless solution was stirred for 45 min at room temperature during which the solution turned light yellow. The solution was then warmed to 75° C. and stirred overnight and allowed to cool. After workup with dichloromethane/water, the combined organic phases were evaporated to dryness. The orange solid was triturated with ethyl acetate and filtered to give 1.27 g of a white solid. The mother liquors were concentrated and the cristallized material was again filtered to yield an additional 0.55 g of product. One obtains a total yield of 1.82 g (81%) of the title compound as a crystalline white solid, MS: m/e=227.3 (M+H⁺).

Step 2: (3aSR, 6aRS)-3-Methyl-2-oxo-hexahydro-cyclopentaimidazole-1-carboxylic acid tert-butyl ester

To a solution of (3aSR, 6aRS)-2-oxo-hexahydro-cyclopentaimidazole-1-carboxylic acid tert-butyl ester (Example 106, step 1) (1.82 g, 8.04 mmol) in 30 ml of DMF was added a 60% suspension of sodium hydride in mineral oil (386 mg, 9.65 mmol, 1.2 equiv.). The suspension was stirred for 45 minutes at room temperature (gas evolution), then iodomethane (0.604 ml, 9.65 mmol, 1.2 equiv.) was added and the mixture was stirred at room temperature overnight. After concentration in vaccuo and workup with ethyl acetate/water, 2.05 g of a yellow oil were obtained containing mineral-oil drops which was directly used in the next step without further characterisation.

Step 3: (3aRS, 6aSR)-1-Methyl-hexahydro-cyclopentaimidazol-2-one

To a solution of (3aSR, 6aRS)-3-methyl-2-oxo-hexahydro-cyclopentaimidazole-1-carboxylic acid tert-butyl ester (Example 106, step 2) (1.99 g, 8.28 mmol) in 30 ml of dichloromethane was added trifluoroacetic acid (7.55 g, 5.1 ml, 66.3 mmol, 8 equiv.) and the yellow solution was stirred at for 5 h at room temperature. The reaction mixture was quenched by addition of saturated sodium bicarbonate solution and the pH of the aqueous phase was set to 9. After workup with dichloromethane/water, the organic phases were dried, filtered and concentrated in vaccuo to yield 1.07 g of an off-white solid, which was taken up in cold ethyl acetate and filtered to yield the title compound (822 mg, 71%) as a crystalline white solid which was directly used in the next step without further characterisation.

Step 4: (3aRS, 6aSR)-1-methyl-3-(5-(phenylethynyl) pyridin-2-yl)hexahydrocyclopenta[d]imidazol-2(1H)-one

To a suspension of 2-bromo-5-(phenylethynyl)pyridine (Example 96, step 1) (55.0 mg, 0.213 mmol), (3aR,6aS)-1-methylhexahydrocyclopenta[d]imidazol-2(1H)-one (Example 106, step 3) (35.8 mg, 0.256 mmol, 1.2 equiv.), 139 mg cesium carbonate (139 mg, 0.426 mmol, 2 equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos) (5 mg, 0.008 mmol, 0.04 equiv.) in 1 ml of toluene was added under argon atmosphere tris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃) (4 mg, 0.0046 mmol, 0.02 equiv.). The mixture was stirred overnight at 70° C. The mixture was directly loaded on a 20 g silicagel column and was eluted with a heptane to 33% ethylacetate in heptane gradient to yield the title compound (49 mg, 73%) as an amorphous light-yellow solid, MS: m/e=318.1 (M+H+).

Example 107 (RS)-4-tert-Butyl-3-methyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=334.1 (M+H⁺), using procedures similar to those described in Example 106 starting from (rac)-2-(tert-butoxycarbonylamino-methyl)-3,3-dimethyl-butyric acid instead of (rac)-cis-2-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid.

Examples 108 1-[5-(3-Fluoro-phenylethynyl)-3-methyl-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

Step 1: 4,4-Dimethyl-1-(3-methyl-5-trimethylsilanylethynyl-pyridin-2-yl)-imidazolidin-2-one

The title compound was obtained as a yellow solid, MS: m/e=302.1 (M+H⁺), using chemistry similar to that described in Example 37, step 2 from 2-bromo-3-methyl-5-trimethylsilanylethynyl-pyridine (Example 41, step 1) and 4,4-dimethyl-imidazolidin-2-one (CAS 24572-33-6).

Step 2: 1-[5-(3-Fluoro-phenylethynyl)-3-methyl-pyridin-2-yl]-4,4-dimethyl-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=324.4 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 4,4-dimethyl-1-(3-methyl-5-trimethylsilanylethynyl-pyridin-2-yl)-imidazolidin-2-one (Example 108, step 1) and 1-fluoro-3-iodobenzene.

Step 3: 1-[5-(3-Fluoro-phenylethynyl)-3-methyl-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=338.3 (M+H⁺), using chemistry similar to that described in Example 16 from 1-[5-(3-fluoro-phenylethynyl)-3-methyl-pyridin-2-yl]-4,4-dimethyl-imidazolidin-2-one (Example 108, step 2) and iodomethane.

Example 109 (3aSR,6aRS)-1-[5-(3-Fluoro-phenylethynyl)-pyridin-2-yl]-3-methyl-hexahydro-cyclopenta-imidazol-2-one

Step 1: (3aRS,6aSR)-1-Methyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-hexahydro-cyclopenta-imidazol-2-one

The title compound, an off-white solid, MS: m/e=314.1 (M+H⁺), was prepared in accordance with the general method of example 106, step 4 starting from 2-bromo-5-((trimethylsilyl)ethynyl)-pyridine (Example 37, step 1) and (3aRS,6aSR)-1-methylhexahydrocyclopenta[d]imidazol-2(1H)-one (Example 106, step 3).

Step 2: (3aSR,6aRS)-1-[5-(3-Fluoro-phenylethynyl)-pyridin-2-yl]-3-methyl-hexahydro-cyclopenta-imidazol-2-one

The title compound, a light yellow oil, MS: m/e=336.2 (M+H⁺), was prepared in accordance with the general method of Example 37, step 3 starting from (3aRS,6aSR)-1-methyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-hexahydro-cyclopenta-imidazol-2-one (Example 109, step 1) and 1-fluoro-3-iodobenzene.

Example 110 1-[3-Fluoro-5-(4-fluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

Step 1: 1-(3-Fluoro-5-iodo-pyridin-2-yl)-4,4-dimethyl-imidazolidin-2-one

2,3-Difluoro-5-iodopyridine (300 mg, 1.24 mmol) was dissolved in 2 ml toluene. (140 mg, 1.24 mmol, 1 equiv.) 4,4-Dimethylimidazolidin-2-one (CAS 24572-33-6) and cesium carbonate (650 mg, 1.99 mmol, 1.6 equiv.) were added and the mixture was heated to 100° C. for 4 hours. The reaction mixture was loaded directly onto a silica gel column and purified by flash chromatography eluting with an ethyl acetate:heptane gradient 0:100 to 100:0. The desired 1-(3-fluoro-5-iodo-pyridin-2-yl)-4,4-dimethyl-imidazolidin-2-one (205 mg, 49% yield) was obtained as a white solid, MS: m/e=336.1 (M+H⁺).

Step 2: 1-(3-Fluoro-5-iodo-pyridin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one

The title compound, a yellow oil, MS: m/e=350.0 (M+H⁺), was prepared in accordance with the general method of Example 16 from 1-(3-fluoro-5-iodo-pyridin-2-yl)-4,4-dimethyl-imidazolidin-2-one (Example 110, step 1) and iodomethane.

Step 3: 1-[3-Fluoro-5-(4-fluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=342.1 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from 1-(3-fluoro-5-iodo-pyridin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example 110, step 2) and 1-ethynyl-4-fluorobenzene.

Example 111 1-[3-Fluoro-5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=342.1 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from 1-(3-fluoro-5-iodo-pyridin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example 110, step 2) and 1-ethynyl-3-fluorobenzene.

Example 112 6-[5-(4-Fluoro-phenylethynyl)-pyridin-2-yl]-4-methyl-4,6-diaza-spiro[2.4]heptan-5-one

Step 1: 4-Methyl-4,6-diaza-spiro[2.4]heptan-5-one

The title compound was obtained as a white solid using procedures similar to those described in Example 106, step 1 to 3 starting from 1-((tert-butoxycarbonylamino)methyl)cyclopropanecarboxylic acid instead of (rac)-cis-2-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid.

Step 2: 4-Methyl-6-(5-trimethylsilanylethynyl-pyridin-2-yl)-4,6-diaza-spiro[2.4]heptan-5-one

The title compound was obtained as a white solid, MS: m/e=300.2 (M+H⁺), using chemistry similar to that described in Example 37, step 2 from 2-bromo-5-trimethylsilanylethynyl-pyridine (Example 37, step 1) and 4-methyl-4,6-diaza-spiro[2.4]heptan-5-one (Example 112, step 1).

Step 3: 6-[5-(4-Fluoro-phenylethynyl)-pyridin-2-yl]-4-methyl-4,6-diaza-spiro[2.4]heptan-5-one

The title compound was obtained as a light yellow solid, MS: m/e=322.2 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 4-methyl-6-(5-trimethylsilanylethynyl-pyridin-2-yl)-4,6-diaza-spiro[2.4]heptan-5-one (Example 112, step 2) and 1-fluoro-4-iodobenzene.

Example 113 6-[5-(3-Fluoro-phenylethynyl)-pyridin-2-yl]-4-methyl-4,6-diaza-spiro[2.4]heptan-5-one

The title compound was obtained as a light brown solid, MS: m/e=322.2 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 4-methyl-6-(5-trimethylsilanylethynyl-pyridin-2-yl)-4,6-diaza-spiro[2.4]heptan-5-one (Example 112, step 2) and 1-fluoro-3-iodobenzene.

Example 114 (RS)-5-Methoxy-6,6-dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

Step 1: (RS)-3-Benzyloxycarbonylamino-2-methoxy-propionic acid methyl ester

The title compound was obtained using chemistry similar to that described in Example 16 starting from (RS)-3-benzyloxycarbonylamino-2-hydroxy-propionic acid methyl ester, which was directly used in the next step without further characterisation.

Step 2: (RS)-5-Methoxy-6,6-dimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a light yellow oil, MS: m/e=160.2 (M+H⁺), using procedures similar to those described in Example 95, step 2 and Example 72, step 2 from (RS)-3-benzyloxycarbonylamino-2-methoxy-propionic acid methyl ester (Example 114, step 1).

Step 3: (RS)-5-Methoxy-6,6-dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

The title compound was obtained as a light yellow oil, MS: m/e=337.3 (M+H⁺), using chemistry similar to that described in Example 37, step 2 from 2-bromo-5-phenylethynyl-pyridine (Example 96, step 1) and (RS)-5-methoxy-6,6-dimethyl-[1,3]oxazinan-2-one (Example 114, step 2).

Example 115 4,4-Dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one

Step 1: 2-Methanesulfonyl-5-phenylethynyl-pyrimidine

Bis-(triphenylphosphine)-palladium(II)dichloride (1.48 g, 2.11 mmol, 0.05 equiv.) was dissolved in 200 ml THF. (10 g, 42.2 mmol) 5-Bromo-2-(methylsulfonyl)pyrimidine and phenylacetylene (9.26 ml, 84.4 mmol, 2 equiv.) were added at room temperature. Triethylamine (17.6 ml, 127 mmol, 3 equiv.), triphenylphosphine (330 mg, 1.3 mmol, 0.03 equiv.) and copper(I)iodide (80 mg, 420 μmol, 0.01 equiv.) were added and the mixture was stirred for 4 hours at 65° C. The reaction mixture was cooled and extracted with saturated NaHCO₃ solution and two times with EtOAc. The organic layers were extracted with water, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 100:0. The desired 2-methanesulfonyl-5-phenylethynyl-pyrimidine (6.2 g, 57% yield) was obtained as a yellow solid, MS: m/e=259.1 (M+H⁺).

Step 2: 4,4-Dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one

(100 mg, 0.39 mmol) 2-Methanesulfonyl-5-phenylethynyl-pyrimidine (Example 115, step 1) was dissolved in 1 ml dioxane. 4,4-Dimethylpyrrolidin-2-one (53 mg, 465 μmol, 1.2 equiv.) and cesium carbonate (190 mg, 580 μmol, 1.5 equiv.) were added at room temperature. The mixture was stirred for 4 hours at 100° C. The reaction mixture was cooled, evaporated and extracted with saturated NaHCO₃ solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 100:0. The desired 4,4-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one (32 mg, 28% yield) was obtained as a light yellow solid, MS: m/e=292.1 (M+H⁺).

Example 116 5,5-Dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-piperidin-2-one

The title compound was obtained as a brown oil, MS: m/e=306.2 (M+H⁺), using chemistry similar to that described in Example 115, step 2 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (Example 115, step 1) and 5,5-dimethylpiperidin-2-one (CAS 4007-79-8).

Example 117 2-(5-Phenylethynyl-pyrimidin-2-yl)-2-aza-spiro[4.4]nonan-3-one

The title compound was obtained as a light yellow solid, MS: m/e=318.2 (M+H⁺), using chemistry similar to that described in Example 115, step 2 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (Example 115, step 1) and 2-aza-spiro[4.4]nonan-3-one (CAS 75751-72-3).

Example 118 1-[5-(3-Fluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2-one

Step 1: 1-(5-Bromo-pyrimidin-2-yl)-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=270.1/272.2 (M+H⁺), using chemistry similar to that described in Example 115, step 2 from 5-bromo-2-fluoropyrimidine and 4,4-dimethylpyrrolidin-2-one.

Step 2: 1-[5-(3-Fluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=310.2 (M+H⁺), using chemistry similar to that described in Example 115, step 1 from 1-(5-bromo-pyrimidin-2-yl)-4,4-dimethyl-pyrrolidin-2-one (Example 118, step 1) and 1-ethynyl-3-fluoro-benzene.

Example 119 1-[5-(3-Chloro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2-one

Step 1: 2-Chloro-5-(3-chloro-phenylethynyl)-pyrimidine

The title compound was obtained as a light brown solid, MS: m/e=248/250 (M+H⁺), using chemistry similar to that described in Example 115, step 1 from 2-chloro-5-iodopyrimidine and 1-chloro-3-ethynyl-benzene.

Step 2: 1-[5-(3-Chloro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=326.3/328.3 (M+H⁺), using chemistry similar to that described in Example 115, step 2 from 2-chloro-5-(3-chloro-phenylethynyl)-pyrimidine (Example 119, step 1) and 4,4-dimethylpyrrolidin-2-one.

Example 120

1-[5-(4-Fluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2-one

Step 1: 2-Bromo-5-trimethylsilanylethynyl-pyrimidine

2-Bromo-5-iodopyrimidine (1.2 g, 4.2 mmol) was dissolved under nitrogen in 25 ml THF. Bis-(triphenylphosphine)-palladium(II)dichloride (300 mg, 420 μmol, 0.1 equiv.), ethynyltrimethylsilane (540 mg, 0.77 ml, 5.48 mmol, 1.3 equiv.), triethylamine (0.85 g, 1.17 ml, 8.4 mmol, 2 equiv.) and copper(I)iodide (40 mg, 210 μmol, 0.05 equiv.) were added and the mixture was stirred for 4 hours at 50° C. The reaction mixture was cooled and evaporated to dryness. The crude product was purified by flash chromatography on silica gel, eluting with an ethyl acetate:heptane gradient 0:100 to 40:60. The desired 2-bromo-5-trimethylsilanylethynyl-pyrimidine (0.75 g, 70% yield) was obtained as a yellow solid, MS: m/e=255/257 (M+H⁺).

Step 2: 4,4-Dimethyl-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one

(200 mg, 0.78 mmol) 2-Bromo-5-trimethylsilanylethynyl-pyrimidine (Example 120, step 1) was dissolved in toluene (7 ml) and 4,4-dimethylpyrrolidin-2-one (89 mg, 0.78 mmol, 1.0 equiv.), cesium carbonate (410 mg, 1.25 mmol, 1.6 equiv.), xantphos (CAS 161265-03-8) (18 mg, 0.03 mmol, 0.04 equiv.) and Pd₂(dba)₃ (14 mg, 0.01 mmol, 0.02 equiv.) were added under nitrogen. The mixture was stirred for 2 hours at 90° C. The crude product was purified by flash chromatography by directly loading the toluene mixture onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 100:0. The desired 4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one (164 mg, 73% yield) was obtained as a light red solid, MS: m/e=288.1 (M+H⁺).

Step 3: 1-[5-(4-Fluoro-phenylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-one

4,4-Dimethyl-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one (Example 120, step 2) (30 mg, 0.1 mmol) was dissolved in DMF (1 ml). 1-Fluoro-4-iodobenzene (32 mg, 0.14 mmol, 1.4 equiv.), Et₃N (43 μl, 0.31 mmol, 3 equiv.), Bis-(triphenylphosphine)-1-palladium(II)dichloride (4 mg, 5.2 μmol, 0.05 equiv.) and copper(I)iodide (0.6 mg, 3.1 μmol, 0.03 equiv.) were added under nitrogen and the mixture was heated to 70° C. TBAF 1M in THF (115 μl, 0.115 mmol, 1.1 equiv.) was added dropwise in 20 minutes at 70° C. The reaction mixture was stirred for 30 minutes at 70° C. and evaporated with isolute to dryness. The crude product was purified by flash chromatography with a 20 g silica gel column and eluting with heptane:ethyl acetate 100:0->0:100. The desired 1-[5-(4-fluoro-phenylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-one (24 mg, 73% yield) was obtained as a white solid, MS: m/e=310.1 (M+H⁺).

Example 121 1-[5-(2,5-Difluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a white solid, MS: m/e=328.2 (M+H⁺), using chemistry similar to that described in Example 120, step 3 from 4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one (Example 120, step 2) and 1,4-difluoro-2-iodobenzene.

Example 122 3,4,4-Trimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-imidazolidin-2-one

Step 1: 1-(5-Iodo-pyrimidin-2-yl)-4,4-dimethyl-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=319 (M+H⁺), using chemistry similar to that described in Example 115, step 2 from 2-chloro-5-iodopyrimidine and 4,4-dimethyl-imidazolidin-2-one (CAS 24572-33-6).

Step 2: 1-(5-Iodo-pyrimidin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one

(55 mg, 173 μmol) 1-(5-Iodo-pyrimidin-2-yl)-4,4-dimethyl-imidazolidin-2-one (Example 122, step 1) was dissolved in DMF (1 ml) and cooled to 0-5° C. NaH (55%) (9 mg, 225 μmol, 1.3 equiv.) was added and the mixture was stirred for 30 min at 0-5° C. Iodomethane (13 μl, 200 μmol, 1.2 equiv.) was added and the mixture was stirred for 30 min without cooling bath. The reaction mixture was treated with sat. NaHCO₃ solution and extracted twice with a small volume of CH₂Cl₂. The organic layers were loaded directly to silica gel column and the crude material was purified by flash chromatography on silica gel (20 gr, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired 1-(5-iodo-pyrimidin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (31 mg, 54% yield) was obtained as a white solid, MS: m/e=333.1 (M+H⁺).

Step 3: 3,4,4-Trimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-imidazolidin-2-one

The title compound was obtained as a yellow oil, MS: m/e=307.4 (M+H⁺), using chemistry similar to that described in Example 115, step 1 from 1-(5-iodo-pyrimidin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example 122, step 2) and phenylacetylene.

Example 123 1-[5-(3-Fluoro-phenylethynyl)-pyrimidin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=325.2 (M+H⁺), using chemistry similar to that described in Example 115, step 1 from 1-(5-iodo-pyrimidin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example 122, step 2) and 1-ethynyl-3-fluoro-benzene.

Example 124 1-[5-(2,5-Difluoro-phenylethynyl)-pyrimidin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

Step 1: 4,4-Dimethyl-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-imidazolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=289.0 (M+H⁺), using chemistry similar to that described in Example 120, step 2 from 2-bromo-5-trimethylsilanylethynyl-pyrimidine (Example 120, step 1) and 4,4-dimethyl-imidazolidin-2-one (CAS 24572-33-6).

Step 2: 1-[5-(2,5-Difluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-imidazolidin-2-one

The title compound was obtained as a light brown solid, MS: m/e=329.2 (M+H⁺), using chemistry similar to that described in Example 120, step 3 from 4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-imidazolidin-2-one (Example 124, step 1) and 1,4-difluoro-2-iodobenzene.

Step 3: 1-[5-(2,5-Difluoro-phenylethynyl)-pyrimidin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

The title compound was obtained as a white solid, MS: m/e=343.1 (M+H⁺), using chemistry similar to that described in Example 122, step 2 from 1-[5-(2,5-difluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-imidazolidin-2-one (Example 124, step 2) and iodomethane.

Example 125

1-[5-(4-Fluoro-phenylethynyl)-pyrimidin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

The title compound was obtained as a light brown solid, MS: m/e=325.2 (M+H⁺), using chemistry similar to that described in Example 115, step 1 from 1-(5-iodo-pyrimidin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example 122, step 2) and 1-ethynyl-4-fluoro-benzene.

Example 126 1-[5-(3,4-Difluoro-phenylethynyl)-pyrimidin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one

The title compound was obtained as a light brown solid, MS: m/e=343.1 (M+H⁺), using chemistry similar to that described in Example 115, step 1 from 1-(5-iodo-pyrimidin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example 122, step 2) and 4-ethynyl-1,2-difluoro-benzene.

Example 127 (RS)-3-Methoxy-4,4-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one

Step 1: (RS)-4-Iodo-N-(5-iodo-pyrimidin-2-yl)-2-methoxy-3,3-dimethyl-butyramide

The title compound was obtained as an orange solid, MS: m/e=476.0 (M+H⁺), using chemistry similar to that described in patent WO9637466, page 17, step 2 starting from (RS)-3-methoxy-4,4-dimethyl-dihydro-furan-2-one (CAS 100101-82-4) instead of 3-t-butylcarbamoyloxy-tetrahydrofuran-2-one and by using 2-amino-5-iodopyrimidine instead of 2-amino-4-trifluoromethylpyridine.

Step 2: (RS)-1-(5-Iodo-pyrimidin-2-yl)-3-methoxy-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=348.0 (M+H⁺), using chemistry similar to that described in patent WO9637466, page 17, step 3 from (RS)-4-iodo-N-(5-iodo-pyrimidin-2-yl)-2-methoxy-3,3-dimethyl-butyramide (Example 127, step 1).

Step 3: (RS)-3-Methoxy-4,4-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=322.2 (M+H⁺), using chemistry similar to that described in Example 115, step 1 from (RS)-1-(5-iodo-pyrimidin-2-yl)-3-methoxy-4,4-dimethyl-pyrrolidin-2-one (Example 127, step 2) and phenylacetylene.

Example 128

(5R or 5S)-5-Methoxymethyl-3-(5-phenylethynyl-pyrimidin-2-yl)-oxazolidin-2-one

The title compound, a light yellow solid, MS: m/e=322.3 (M+H⁺), was prepared by separation of (RS)-3-methoxy-4,4-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one (Example 127) using a chiral column (chiralpak AD with heptane:isopropanol 90:10 as solvent).

Example 129 (5S or 5R)-5-Methoxymethyl-3-(5-phenylethynyl-pyrimidin-2-yl)-oxazolidin-2-one

The title compound, a light yellow solid, MS: m/e=322.3 (M+H⁺), was prepared by separation of (RS)-3-methoxy-4,4-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one (Example 127) using a chiral column (chiralpak AD with heptane:isopropanol 90:10 as solvent).

Example 130 (RS)-1-[5-(3-Fluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a yellow solid, MS: m/e=340.2 (M+H⁺), using chemistry similar to that described in Example 115, step 1 from (RS)-1-(5-iodo-pyrimidin-2-yl)-3-methoxy-4,4-dimethyl-pyrrolidin-2-one (Example 127, step 2) and 1-ethynyl-3-fluoro-benzene.

Example 131 (R or S)-1-[5-(3-Fluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one

The title compound, a white solid, MS: m/e=340.3 (M+H⁺), was prepared by separation of (RS)-1-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one (Example 130) using a chiral column (chiralpak AD with heptane:isopropanol 90:10 as solvent).

Example 132 (S or R)-1-[5-(3-Fluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one

The title compound, a white solid, MS: m/e=340.3 (M+H⁺), was prepared by separation of (RS)-1-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one (Example 130) using a chiral column (chiralpak AD with heptane:isopropanol 90:10 as solvent).

Example 133 (R or S)-1-[5-(2,5-Difluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one

Step 1: (RS)-3-Methoxy-4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one

The title compound was obtained as a light brown solid, MS: m/e=318.1 (M+H⁺), using chemistry similar to that described in Example 115, step 1 from (RS)-1-(5-iodo-pyrimidin-2-yl)-3-methoxy-4,4-dimethyl-pyrrolidin-2-one (Example 127, step 2) and ethynyl-trimethyl-silane.

Step 2: (RS)-1-[5-(2,5-Difluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one

The title compound was obtained as a yellow solid, MS: m/e=358.1 (M+H⁺), using chemistry similar to that described in Example 120, step 3 from (RS)-3-methoxy-4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one (Example 133, step 1) and 1,4-difluoro-2-iodo-benzene.

Step 3: (R or S)-1-[5-(2,5-Difluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one

The title compound, a white solid, MS: m/e=358.1 (M+H⁺), was prepared by separation of (RS)-1-[5-(2,5-difluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one (Example 133, step 2) using a chiral column (Reprosil Chiral NR with heptane:EtOH 70:30 as solvent).

Example 134 4,4-Dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-piperidin-2-one

Step 1: 4,4-Dimethyl-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-piperidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=302.2 (M+H⁺), using chemistry similar to that described in Example 115, step 1 from 2 from 2-bromo-5-trimethylsilanylethynyl-pyrimidine (Example 120, step 1) and 4,4-dimethyl-piperidin-2-one (CAS 55047-81-9).

Step 2: 4,4-Dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-piperidin-2-one

The title compound was obtained as a white solid, MS: m/e=306.3 (M+H⁺), using chemistry similar to that described in Example 120, step 3 from 4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-piperidin-2-one (Example 134, step 1) and iodobenzene.

Example 135 1-[5-(3-Fluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-piperidin-2-one

The title compound was obtained as a white solid, MS: m/e=324.2 (M+H⁺), using chemistry similar to that described in Example 120, step 3 from 4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-piperidin-2-one (Example 134, step 1) and 1-fluoro-3-iodobenzene.

Example 136

1-[5-(2,5-Difluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-piperidin-2-one

The title compound was obtained as a light yellow solid, MS: m/e=342.3 (M+H⁺), using chemistry similar to that described in Example 120, step 3 from 4,4-dimethyl-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-piperidin-2-one (Example 134, step 1) and 2,5-difluoro-3-iodobenzene.

Example 137 3,4,4-Trimethyl-5′-phenylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one

Step 1: 4,4-Dimethyl-tetrahydro-pyrimidin-2-one

(3.4 g, 14.3 mmol) (3-Amino-3-methyl-butyl)-carbamic acid tert-butyl ester hydrochloride was dissolved in THF (60 ml) and KOtBu (6.4 g, 57.1 mmol, 4 equiv.) was added. The mixture was stirred for 16 hours at 60° C. and evaporated then with isolute to dryness. The crude product was purified by flash chromatography by directly loading the residue onto a silica gel column and eluting with an ethyl acetate:methanol gradient 100:0 to 70:30. The desired 4,4-dimethyl-tetrahydro-pyrimidin-2-one (1.65 g, 90% yield) was obtained as a light yellow solid, MS: m/e=129.1 (M+H⁺).

Step 2: 4,4-Dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one

The title compound was obtained as a brown solid, MS: m/e=303.2 (M+H⁺), using chemistry similar to that described in Example 120, step 2 from 2 from 2-bromo-5-trimethylsilanylethynyl-pyrimidine (Example 120, step 1) and 4,4-dimethyl-tetrahydro-pyrimidin-2-one (Example 137, step 1).

Step 3: 4,4-Dimethyl-5′-phenylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one

The title compound was obtained as a yellow solid, MS: m/e=329.2 (M+H⁺), using chemistry similar to that described in Example 120, step 3 from 4,4-dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one (Example 137, step 2) and iodobenzene.

Step 4: 3,4,4-Trimethyl-5′-phenylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one

The title compound was obtained as a light yellow solid, MS: m/e=321.1 (M+H⁺), using chemistry similar to that described in Example 122, step 2 from 4,4-dimethyl-5′-phenylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one (Example 137, step 3) and iodomethane.

Example 138 5′-(3-Fluoro-phenylethynyl)-3,4,4-trimethyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one

Step 1: 5′-(3-Fluoro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one

The title compound was obtained as a light brown solid, MS: m/e=325.2 (M+H⁺), using chemistry similar to that described in Example 120, step 3 from 4,4-dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one (Example 137, step 2) and 1-fluoro-3-iodobenzene.

Step 2: 5′-(3-Fluoro-phenylethynyl)-3,4,4-trimethyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one

The title compound was obtained as a yellow oil, MS: m/e=339.2 (M+H⁺), using chemistry similar to that described in Example 122, step 2 from 5′-(3-fluoro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one (Example 138, step 1) and iodomethane.

Example 139 5′-(2,5-Difluoro-phenylethynyl)-3,4,4-trimethyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one

Step 1: 5′-(2,5-Difluoro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one

The title compound was obtained as a light brown solid, MS: m/e=343.1 (M+H⁺), using chemistry similar to that described in Example 120, step 3 from 4,4-dimethyl-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one (Example 137, step 2) and 1,4-difluoro-2-iodobenzene.

Step 2: 5′-(2,5-Difluoro-phenylethynyl)-3,4,4-trimethyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one

The title compound was obtained as a light yellow solid, MS: m/e=357.2 (M+H⁺), using chemistry similar to that described in Example 122, step 2 from 5′-(2,5-difluoro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyrimidinyl-2-one (Example 139, step 1) and iodomethane.

Example 140 3-Isopropyl-4,4-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-imidazolidin-2-one

Step 1: 1-(5-Iodo-pyrimidin-2-yl)-3-isopropyl-4,4-dimethyl-imidazolidin-2-one

The title compound was obtained as a light yellow oil, MS: m/e=361.0 (M+H⁺), using chemistry similar to that described in Example 122, step 2 from 1-(5-iodo-pyrimidin-2-yl)-4,4-dimethyl-imidazolidin-2-one (Example 122, step 1) and 2-iodopropane.

Step 2: 3-Isopropyl-4,4-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-imidazolidin-2-one

The title compound was obtained as a light brown solid, MS: m/e=335.2 (M+H⁺), using chemistry similar to that described in Example 115, step 1 from 1-(5-iodo-pyrimidin-2-yl)-3-isopropyl-4,4-dimethyl-imidazolidin-2-one (Example 140, step 1) and phenylacetylene.

Example 141 1-[5-(3-Fluoro-phenylethynyl)-pyrimidin-2-yl]-3-isopropyl-4,4-dimethyl-imidazolidin-2-one

The title compound was obtained as a light brown solid, MS: m/e=353.3 (M+H⁺), using chemistry similar to that described in Example 115, step 1 from 1-(5-iodo-pyrimidin-2-yl)-3-isopropyl-4,4-dimethyl-imidazolidin-2-one (Example 140, step 1) and 1-ethynyl-3-fluorobenzene.

Example 142

1-[5-(4-Fluoro-phenylethynyl)-pyrimidin-2-yl]-3-isopropyl-4,4-dimethyl-imidazolidin-2-one

The title compound was obtained as a light brown solid, MS: m/e=353.3 (M+H⁺), using chemistry similar to that described in Example 115, step 1 from 1-(5-iodo-pyrimidin-2-yl)-3-isopropyl-4,4-dimethyl-imidazolidin-2-one (Example 140, step 1) and 1-ethynyl-4-fluorobenzene.

Example 143 1-[5-(4-Fluoro-phenylethynyl)-pyrimidin-2-yl]-3-ethyl-4,4-dimethyl-imidazolidin-2-one

Step 1: 1-(5-Bromo-pyrimidin-2-yl)-4,4-dimethyl-imidazolidin-2-one

The title compound was obtained as a light brown solid, MS: m/e=271.1/273.1 (M+H⁺), using chemistry similar to that described in Example 120, step 2 from 5-bromo-2-iodopyrimidine and 4,4-dimethyl-imidazolidin-2-one (CAS 24572-33-6).

Step 2: 1-(5-Bromo-pyrimidin-2-yl)-3-ethyl-4,4-dimethyl-imidazolidin-2-one

The title compound was obtained as a brown solid, MS: m/e=299.2/301.2 (M+H⁺), using chemistry similar to that described in Example 122, step 2 from 1-(5-bromo-pyrimidin-2-yl)-4,4-dimethyl-imidazolidin-2-one (Example 143, step 1) and ethyl iodide.

Step 3: 1-(5-Iodo-pyrimidin-2-yl)-3-ethyl-4,4-dimethyl-imidazolidin-2-one

(350 mg, 1.17 mmol) 1-(5-Bromo-pyrimidin-2-yl)-3-ethyl-4,4-dimethyl-imidazolidin-2-one (Example 143, step 2) was dissolved in dioxane (20 ml) and sodium iodide (700 mg, 4.68 mmol, 4 equiv.), copper(I)iodide (21 mg, 0.234 mmol, 0.2 equiv.) and trans-N,N′-dimethylcyclohexane-1,2-diamine (33 mg, 37 μl, 0.234 mmol, 0.2 equiv.) were added. The mixture was stirred for 16 hours at 100° C. The reaction mixture was cooled and extracted with saturated NaHCO₃ solution and two times ethyl acetate. The organic layers were extracted with brine, dried over sodium sulfate and evaporated to dryness. The desired 1-(5-iodo-pyrimidin-2-yl)-3-ethyl-4,4-dimethyl-imidazolidin-2-one (350 mg, 86% yield) was obtained as a brown solid, MS: m/e=347.0 (M+H⁺) and was used without further purification in the next step.

Step 4: 1-[5-(4-Fluoro-phenylethynyl)-pyrimidin-2-yl]-3-ethyl-4,4-dimethyl-imidazolidin-2-one

The title compound was obtained as a brown solid, MS: m/e=339.3 (M+H⁺), using chemistry similar to that described in Example 115, step 1 from 1-(5-iodo-pyrimidin-2-yl)-3-ethyl-4,4-dimethyl-imidazolidin-2-one (Example 143, step 3) and 1-ethynyl-4-fluorobenzene.

Example 144 1-[5-(3-Fluoro-phenylethynyl)-pyrimidin-2-yl]-3-ethyl-4,4-dimethyl-imidazolidin-2-one

The title compound was obtained as a light brown solid, MS: m/e=339.3 (M+H⁺), using chemistry similar to that described in Example 115, step 1 from 1-(5-iodo-pyrimidin-2-yl)-3-ethyl-4,4-dimethyl-imidazolidin-2-one (Example 143, step 3) and 1-ethynyl-3-fluorobenzene.

Example 145 (RS)-5,6,6-Trimethyl-3-(5-phenylethynyl-pyrimidin-2-yl)-[1,3]oxazinan-2-one

Step 1: (RS)-(3-Hydroxy-2,3-dimethyl-butyl)-carbamic acid tert-butyl ester

The title compound was obtained as a colorless oil, MS: m/e=218.3 (M+H⁺), using chemistry similar to that described in Example 95, step 2 from methyl 3-(tert-butoxycarbonylamino)-2-methylpropanoate (CAS 182486-16-4).

Step 2: (RS)-5,6,6-Trimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a yellow solid, MS: m/e=144.0 (M+H⁺), using chemistry similar to that described in Example 72, step 2 from (RS)-(3-hydroxy-2,3-dimethyl-butyl)-carbamic acid tert-butyl ester (Example 145, step 1).

Step 3: 2-Bromo-5-phenylethynyl-pyrimidine

The title compound was obtained as a white solid using chemistry similar to that described in Example 120, step 1 from 2-bromo-5-iodopyrimidine and phenylacetylene.

Step 4: (RS)-5,6,6-Trimethyl-3-(5-phenylethynyl-pyrimidin-2-yl)-[1,3]oxazinan-2-one

The title compound was obtained as a yellow solid, MS: m/e=322.2 (M+H⁺), using chemistry similar to that described in Example 120, step 2 from 2-bromo-5-phenylethynyl-pyrimidine (Example 145, step 3) and (RS)-5,6,6-trimethyl-[1,3]oxazinan-2-one (Example 145, step 2).

Example 146 (RS)-3-[5-(2,5-Difluoro-phenylethynyl)-pyrimidin-2-yl]-5,6,6-trimethyl-[1,3]oxazinan-2-one

Step 1: (RS)-5,6,6-Trimethyl-3-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-[1,3]oxazinan-2-one

The title compound was obtained as a brown solid, MS: m/e=318.1 (M+H⁺), using chemistry similar to that described in Example 120, step 2 from 2-bromo-5-trimethylsilanylethynyl-pyrimidine (Example 120, step 1) and (RS)-5,6,6-trimethyl-[1,3]oxazinan-2-one (Example 145, step 2).

Step 2: (RS)-3-[5-(2,5-Difluoro-phenylethynyl)-pyrimidin-2-yl]-5,6,6-trimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a white solid, MS: m/e=358.4 (M+H⁺), using chemistry similar to that described in Example 120, step 3 from (RS)-5,6,6-trimethyl-3-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-[1,3]oxazinan-2-one (Example 146, step 1) and 1,4-difluoro-2-iodobenzene.

Example 147 4-Methyl-6-(5-phenylethynyl-pyrimidin-2-yl)-4,6-diaza-spiro[2.4]heptan-5-one

Step 1: 4-Methyl-4,6-diaza-spiro[2.4]heptan-5-one

The title compound was obtained as a white solid using procedures similar to those described in Example 106, step 1 to 3 from starting from 1-((tert-butoxycarbonylamino)methyl)cyclopropanecarboxylic acid instead of (rac)-cis-2-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid.

Step 2: 4-Methyl-6-(5-phenylethynyl-pyrimidin-2-yl)-4,6-diaza-spiro[2.4]heptan-5-one

The title compound was obtained as a white solid, MS: m/e=305.3 (M+H⁺), using chemistry similar to that described in Example 120, step 2 from 2-bromo-5-phenylethynyl-pyrimidine (Example 145, step 3) and 4-methyl-4,6-diaza-spiro[2.4]heptan-5-one (Example 147, step 1).

Example 148 (RS)-3-[5-(3-Fluoro-phenylethynyl)-pyrimidin-2-yl]-5,6,6-trimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a yellow solid, MS: m/e=340.1 (M+H⁺), using chemistry similar to that described in Example 120, step 3 from (RS)-5,6,6-trimethyl-3-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-[1,3]oxazinan-2-one (Example 146, step 1) and 1-fluoro-3-iodobenzene.

Example 149 (RS)-3-[5-(4-Fluoro-phenylethynyl)-pyrimidin-2-yl]-5,6,6-trimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a yellow solid, MS: m/e=340.1 (M+H⁺), using chemistry similar to that described in Example 120, step 3 from (RS)-5,6,6-trimethyl-3-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-[1,3]oxazinan-2-one (Example 146, step 1) and 1-fluoro-4-iodobenzene.

Example 150 4,4-Dimethyl-1-(6-(phenylethynyl)pyridazin-3-yl)pyrrolidin-2-one

To a solution of 3-chloro-6-(phenylethynyl)pyridazine (CAS 77778-15-5) (180 mg, 839 mmol) and 4,4-dimethylpyrrolidin-2-one (CAS 66899-02-3) (142 mg, 1.26 mmol, 1.5 equiv.) in 2 ml of DMF were added cesium carbonate (546 mg, 1.68 mmol, 2 equiv.). The suspension was heated 16 hours at 120° C. and then allowed to cool to room temperature. Ethyl acetate (10 ml) were added and the unsoluble salts were filtered off. After concentration in vaccuo, the residue was dissolved in 10 ml of ethyl acetate. Silicagel (4 g) were added and the suspension was evaporated to dryness. The silicagel with the adsorbed crude mixture was loaded onto a 20 g silicagel flash chromatography column and eluted three min. with heptane followed by a heptane to 45% ethyl acetate/heptane gradient over 25 min to yield 36 mg (15% yield) of the title compound as a cristalline yellow solid, MS: m/e=292.3 (M+H⁺).

Example 151 4,4-Dimethyl-1-(6-(phenylethynyl)pyridazin-3-yl)piperidin-2-one

Step 1: 3-Iodo-6-(phenylethynyl)pyridazine

To a solution of 100 mg (0.466 mmol) of 3-chloro-6-(phenylethynyl)pyridazine in 5 ml of acetonitrile were added sodium iodide (209 mg, 1.4 mmol, 3 equiv.), acetic acid (56 mg, 53.3 ml, 0.93 mmol, 2 equiv.), and 95% sulfuric acid (4.6 mg, 2.5 ml, 0.47 mmol, 1 equiv.). The orange solution was stirred for 8 hours at 70° C. and then left to cool overnight. After standard workup with ethyl acetate/water, the residue was adsorbed onto 4 g of silicagel and purified by flash chromatography over a 20 g silicagel column over a heptane to 50% ethyl acetate in heptane gradient to yield 82 mg (58% yield) of the title compound as a crystalline light yellow solid, MS: m/e=307.1 (M+H⁺).

Step 2: 4,4-Dimethyl-1-(6-(phenylethynyl)pyridazin-3-yl)piperidin-2-one

To a well stirred suspension of 3-iodo-6-(phenylethynyl)pyridazine (Example 151, step 1) (80 mg, 261 μmol), 4,4-dimethylpiperidin-2-one (66.5 mg, 314 μmol, 1.2 equiv.) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos) (6.05 mg, 10.5 μmol, 0.04 equiv.) in 2 ml of toluene were added under argon atmosphere tris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃), (4.79 mg, 5.23 μmol, 0.02 equiv.) and the mixture was stirred for 4 hours at 100° C. The crude mixture was directly purified by flash chromatography over a 20 g silicagel column using a heptane to 50% ethyl acetate in heptane gradient, and yielded 18 mg (23% yield) of the title compound as a white solid, MS: m/e=306.2 (M+H⁺).

Example 152 5,5-Dimethyl-3-(6-(phenylethynyl)pyridazin-3-yl)oxazolidin-2-one

Step 1: 2-Methyl-1-(6-phenylethynyl-pyridazin-3-ylamino)-propan-2-ol

A solution of 3-chloro-6-(phenylethynyl)pyridazine (CAS 77778-15-5) (300 mg, 1.4 mmol) and 1-amino-2-methylpropan-2-ol (137 mg, 147 μl, 1.54 mmol, 1.1 equiv.) in 3 ml of pyridine was heated 20 hours at 120° C. in a sealed tube. The solvent was removed in vaccuo. The residue was taken up in ethyl acetate/methanol, adsorbed onto 4 g of silica and purified on a 20 g flash chromatography column using a heptane to ethyl acetate gradient to yield 90 mg (24% yield) of the title compound as a crystalline light yellow solid, MS: m/e=268.2 (M+H⁺).

Step 2: 5,5-Dimethyl-3-(6-(phenylethynyl)pyridazin-3-yl)oxazolidin-2-one

A solution of 2-methyl-1-(6-(phenylethynyl)pyridazin-3-ylamino)propan-2-ol (Example 152, step 1) (90 mg, 337 μmol) and triethylamine (102 mg, 141 μl, 1.01 mmol, 3 equiv.) in 4 ml of THF was cooled to 0-5° C. and then triphosgene (99.9 mg, 337 μmol, 1 equiv.) was added and the reaction was stirred for 1 hour at 0-5° C. The mixture was quenched with 5 ml of 5% sodium bicarbonate solution and worked up with ethyl acetate/water. The crude material was adsorbed onto silicagel and purified by flash chromatography over a heptane to 50% ethyl acetate in heptane gradient to yield the title compound (51 mg, 52% yield) as a crystalline light yellow solid, MS: m/e=294.2 (M+H⁺).

Example 153 6,6-Dimethyl-3-(6-(phenylethynyl)pyridazin-3-yl)-1,3-oxazinan-2-one

Step 1: 2-Methyl-4-(6-phenylethynyl-pyridazin-3-ylamino)-butan-2-ol

A solution of 3-chloro-6-(phenylethynyl)pyridazine (CAS 77778-15-5) (125 mg, 0.582 mmol) and 4-amino-2-methylbutan-2-ol hydrochloride (244 mg, 1.75 mmol, 3 equiv.) and triethylamine (206 mg, 284 ml, 2.04 mmol, 2 equiv.) in 1.25 ml of pyridine was heated 20 hours at 85° C. The solvent was removed in vaccuo. The residue was taken up in ethyl acetate/methanol, adsorbed onto 4 g of silica and purified on a 20 g flash chromatography column using a heptane/ethyl acetate 85:15 to 15:85 gradient to yield 44 mg (27% yield) of the title compound as a crystalline white solid, MS: m/e=282.2 (M+H⁺).

Step 2: 6,6-Dimethyl-3-(6-(phenylethynyl)pyridazin-3-yl)-1,3-oxazinan-2-one

The title compound, a crystalline light yellow solid, MS: m/e=308.3 (M+H⁺), was prepared in accordance with the general method of Example 152, step 2 starting from 2-methyl-4-(6-phenylethynyl-pyridazin-3-ylamino)-butan-2-ol (Example 153, step 1) and triphosgene.

Example 154 3,4,4-Trimethyl-1-(6-(m-tolylethynyl)pyridazin-3-yl)imidazolidin-2-one

Step 1: N-1-(6-Iodo-pyridazin-3-yl)-2-methyl-propane-1,2-diamine

A suspension of 3-chloro-6-iodo-pyridazine (CAS 135034-10-5) (500 mg, 2.08 mmol) and 2-methylpropane-1,2-diamine (220 mg, 262 μl, 2.5 mmol, 1.2 equiv.) in 4 ml of pyridine was heated 16 hours at 100° C. The solvent was removed in vaccuo. The crude material (508 mg) was directly used in the next step.

Step 2: 1-(6-Chloro-pyridazin-3-yl)-4,4-dimethyl-imidazolidin-2-one

To a solution of crude N-1-(6-iodopyridazin-3-yl)-2-methylpropane-1,2-diamine (Example 154, step 1) (580 mg, 1.99 mmol) and pyridine (346 mg, 353 μl, 4.37 mmol, 2.2 equiv.) in 5 ml of dichloromethane were added (1.96 g, 2.1 ml, 3.97 mmol, 2 equiv.) of a 20% solution of phosgene in toluene dropwise at 0-2° C. over a period of 10 min. After stirring for 2 hours at 0-4° C., the reaction was allowed to warm up to room temperature overnight. The mixture was quenched with 5 ml of 5% sodium bicarbonate solution and worked up with dichloromethane/water. The crude material was adsorbed onto silicagel and purified by flash chromatography using a heptane to 80% ethyl acetate in heptane gradient to yield the title compound (where the iodine was completely exchanged for chlorine) (140 mg, 31% yield) as a crystalline white solid, MS: m/e=227.2, 229.4 (M+H⁺).

Step 3: 1-(6-Chloro-pyridazin-3-yl)-3,4,4-trimethyl-imidazolidin-2-one

To a solution of 1-(6-chloropyridazin-3-yl)-4,4-dimethylimidazolidin-2-one (Example 154, step 2) (140 mg, 618 μmol) in DMF (3 ml) was added 60% sodium hydride suspension (37.1 mg, 926 μmol, 1.5 equiv.). After stirring at room temperature for 10 min, iodomethane (132 mg, 57.9 μl, 926 μmol, 1.5 equiv.) was added and the suspension was stirred for 1 hour at room temperature. The solvent was removed in vaccuo and the residue was worked up with ethyl acetate/water. The title compound was obtained as a crystalline light brown solid (129 mg, 87% yield), MS: m/e=241.2, 243.4 (M+H⁺).

Step 4: 1-(6-Iodo-pyridazin-3-yl)-3,4,4-trimethyl-imidazolidin-2-one

The title compound, crystalline light yellow solid (149 mg, 86%), MS: m/e=333.0 (M+H⁺), was prepared from 1-(6-chloro-pyridazin-3-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example 154, step 3) in accordance with the general method of Example 151, step 1 by acid catalyzed chlorine-iodine exchange.

Step 5: 3,4,4-Trimethyl-1-(6-(m-tolylethynyl)pyridazin-3-yl)imidazolidin-2-one

To a solution of 1-(6-iodopyridazin-3-yl)-3,4,4-trimethylimidazolidin-2-one (Example 154, step 4) (75 mg, 226 μmol), 1-ethynyl-3-methylbenzene (44.6 mg, 49.5 μl, 384 μmol, 1.7 equiv.), triethylamine (68.5 mg, 94.4 μl, 677 μmol, 3 equiv.), bis(triphenylphosphine)palladium (II) chloride (9.51 mg, 13.5 μmol, 0.06 equiv.) and triphenylphosphine (1.78 mg, 6.77 μmol, 0.03 equiv.) in 2 ml of THF was added under an Argon atmosphere copper (I) iodide (1.29 mg, 6.77 μmol, 0.03 equiv.). The suspension was warmed to 60° C. for 2 hours, taken up in 5 ml of ethyl acetate and adsorbed on 4 g of silica. Purification by flash chromatography on silicagel using a heptane to 50% ethyl acetate/heptane gradient yielded the title compound as a crystalline light yellow solid (18 mg, 25% yield), MS: m/e=321.2 (M+H⁺).

Example 155 1-(6-((3-Chlorophenyl)ethynyl)pyridazin-3-yl)-3,4,4-trimethylimidazolidin-2-one

The title compound, a crystalline light yellow solid (36 mg, 47% yield), MS: m/e=341.2, 343.3 (M+H⁺), was prepared in accordance with the general method of Example 154, step 5; starting from 1-(6-iodo-pyridazin-3-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example 154, step 4) and 3-chlorophenyl-acetylene.

Example 156 3,4,4-Trimethyl-1-(5-(phenylethynyl)pyrazin-2-yl)imidazolidin-2-one

Step 1: N-1-(5-Iodo-pyrazin-2-yl)-2-methyl-propane-1,2-diamine

To a solution of 2-bromo-5-iodopyrazine (CAS 622392-04-5) (250 mg, 878 μmol) in 0.7 ml of pyridine, was added 2-methylpropane-1,2-diamine (116 mg, 138 μl, 1.32 mmol, 1.5 equiv.) at room temperature. The colorless solution was stirred for 16 hours at 100° C. The reaction mixture was cooled and concentrated in vacuo. The crude material was used directly in the next step.

Step 2: 1-(5-Iodo-pyrazin-2-yl)-4,4-dimethyl-imidazolidin-2-one

The title compound, an off-white solid (72 mg, 26% yield), was prepared in accordance with the general method of Example 154, step 2; starting from N-1-(5-iodo-pyrazin-2-yl)-2-methyl-propane-1,2-diamine (Example 156, step 1) and cyclisation with phosgene. The crude material was directly used in the next step without further characterization.

Step 3: 1-(5-Iodo-pyrazin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one

The title compound, an off-white solid (77 mg, 99% yield), was prepared in accordance with the general method of Example 154, step 3; by alkylation of 1-(5-iodo-pyrazin-2-yl)-4,4-dimethyl-imidazolidin-2-one (Example 156, step 2) with methyl iodide. The crude material was directly used in the next step without further characterization.

Step 4: ′3,4,4-Trimethyl-1-(5-(phenylethynyl)pyrazin-2-yl)imidazolidin-2-one

The title compound, a crystalline light yellow solid (69 mg, 75% yield), MS: m/e=307.3 (M+H⁺), was prepared in accordance with the general method of Example 154, step 5; starting from 1-(5-iodo-pyrazin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example 156, step 3) and phenylacetylene.

Example 157 3,4,4-Trimethyl-1-(5-(pyridin-3-ylethynyl)pyrazin-2-yl)imidazolidin-2-one

The title compound, a crystalline yellow solid, MS: m/e=308.3 (M+H⁺), was prepared in accordance with the general method of Example 154, step 5; starting from 1-(5-iodo-pyrazin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example 156, step 3) and 3-pyridylacetylene.

Example 158 1-(5-((3-Fluorophenyl)ethynyl)pyrazin-2-yl)-3,4,4-trimethylimidazolidin-2-one

The title compound, a crystalline light yellow solid, MS: m/e=325.2 (M+H⁺), was prepared in accordance with the general method of Example 154, step 5; starting from 1-(5-iodo-pyrazin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example 156, step 3) and 3-fluorophenylacetylene.

Example 159 1-(5-((4-Fluorophenyl)ethynyl)pyrazin-2-yl)-3,4,4-trimethylimidazolidin-2-one

The title compound, a light yellow solid, MS: m/e=325.2 (M+H⁺), was prepared in accordance with the general method of example 154, step 5; starting from 1-(5-iodo-pyrazin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (Example 156, step 3) and 4-fluorophenylacetylene.

Example 160 4,4-Dimethyl-1-(5-(pyridin-3-ylethynyl)pyrazin-2-yl)pyrrolidin-2-one

Step 1: 1-(5-Bromo-pyrazin-2-yl)-4,4-dimethyl-pyrrolidin-2-one

To a well stirred suspension of 2-bromo-5-iodopyrazine (300 mg, 1.05 mmol), 4,4-dimethylpiperidin-2-one (155 mg, 1.37 mmol, 1.3 equiv.) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos) (24.4 mg, 0.042 mmol, 0.04 equiv.) in 4 ml of toluene were added under argon atmosphere tris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃), (19.3 mg, 0.021 mmol, 0.02 equiv.) and the mixture was stirred for 5 hours at 100° C. The crude mixture was adsorbed on silicagel and purified by flash chromatography over a 20 g silicagel column using a 2:1 heptane/ethyl acetate mixture as eluant. The title compound (151 mg, 53% yield) was obtained as a white solid, MS: m/e=270.1, 272.1 (M+H⁺).

Step 2: 4,4-Dimethyl-1-(5-(pyridin-3-ylethynyl)pyrazin-2-yl)pyrrolidin-2-one

The title compound, a light yellow solid, MS: m/e=310.4 (M+H⁺), was prepared in accordance with the general method of Example 154, step 5; starting from 1-(5-bromo-pyrazin-2-yl)-4,4-dimethyl-pyrrolidin-2-one (Example 160, step 1) and 3-fluorophenylacetylene.

Example 161 1-(5-((3-Fluorophenyl)ethynyl)pyrazin-2-yl)-4,4-dimethylpiperidin-2-one

Step 1: 1-(5-Bromo-pyrazin-2-yl)-4,4-dimethyl-piperidin-2-one

The title compound, an off-white solid, MS: m/e=284.2, 286.0 (M+H⁺), was prepared in accordance with the general method of Example 160, step 1; starting from 2-bromo-5-iodopyrazine and 4,4-dimethyl-piperidin-2-one.

Step 2: 1-(5-((3-Fluorophenyl)ethynyl)pyrazin-2-yl)-4,4-dimethylpiperidin-2-one

The title compound, an off-white solid, MS: m/e=324.3 (M+H⁺), was prepared in accordance with the general method of Example 154, step 5; starting from 1-(5-bromo-pyrazin-2-yl)-4,4-dimethyl-piperidin-2-one (Example 161, step 1) and 3-fluorophenylacetylene.

Example 162 4,4-Dimethyl-1-(5-(pyridin-3-ylethynyl)pyrazin-2-yl)piperidin-2-one

The title compound, an off-white solid, MS: m/e=307.2 (M+H⁺), was prepared in accordance with the general method of Example 154, step 5; starting from 1-(5-bromo-pyrazin-2-yl)-4,4-dimethyl-piperidin-2-one (Example 161, step 1) and 3-pyridylacetylene.

Example 163 4,4-Dimethyl-1-(5-(phenylethynyl)pyrazin-2-yl)piperidin-2-one

The title compound, a yellow solid, MS: m/e=306.2 (M+H⁺), was prepared in accordance with the general method of Example 154, step 5; starting from 1-(5-bromo-pyrazin-2-yl)-4,4-dimethyl-piperidin-2-one (Example 161, step 1) and phenylacetylene.

Example 164 4,4-Dimethyl-1-(5-(phenylethynyl)pyrazin-2-yl)tetrahydropyrimidin-2(1H)-one

Step 1: 1-(5-Bromo-pyrazin-2-yl)-4,4-dimethyl-tetrahydro-pyrimidin-2-one

The title compound, a light brown solid, MS: m/e=285.0, 287.0 (M+H⁺), was prepared in accordance with the general method of Example 160, step 1; starting from 2-bromo-5-iodopyrazine and 4,4-dimethyl-tetrahydro-pyrimidin-2-one (Example 137, step 1).

Step 2: 4,4-Dimethyl-1-(5-(phenylethynyl)pyrazin-2-yl)tetrahydropyrimidin-2(1H)-one

The title compound, a light yellow solid, MS: m/e=307.3 (M+H⁺), was prepared in accordance with the general method of example 45, step 5; starting from 1-(5-bromo-pyrazin-2-yl)-4,4-dimethyl-tetrahydro-pyrimidin-2-one (Example 164, step 1) and phenylacetylene.

Example 165 3,4,4-Trimethyl-1-(5-(phenylethynyl)pyrazin-2-yl)tetrahydropyrimidin-2(1H)-one

To a solution of 4,4-dimethyl-1-(5-(phenylethynyl)pyrazin-2-yl)tetrahydropyrimidin-2(1H)-one (Example 164, step 2) (30 mg, 0.098 mmol) in 2 ml of DMF was added 60% sodium hydride suspension (4.7 mg, 0.118 mmol, 1.2 equiv.). After stirring at room temperature for 15 min, iodomethane (7.4 ml, 16.7 mg, 0.118 mmol, 1.2 equiv.) was added and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and was worked up with ethyl acetate/water. Flash chromatography over a prepacked 20 g silica column eluting with a heptane to 50% ethyl acetate in heptane gradient yielded the title compound (25.4 mg, 81% yield) as an off-white solid, MS: m/e=321.3 (M+H⁺).

Example 166 1-(5-((3-Fluorophenyl)ethynyl)pyrazin-2-yl)-4,4-dimethyltetrahydropyrimidin-2(1H)-one

The title compound, an off-white solid, MS: m/e=325.3 (M+H⁺), was prepared in accordance with the general method of Example 154, step 5; starting from 1-(5-bromo-pyrazin-2-yl)-4,4-dimethyl-tetrahydro-pyrimidin-2-one (Example 164, step 1) and 3-fluorophenylacetylene.

Example 167 1-(5-((3-Fluorophenyl)ethynyl)pyrazin-2-yl)-3,4,4-trimethyltetrahydropyrimidin-2(1H)-one

The title compound, a light yellow solid, MS: m/e=339.1 (M+H⁺), was prepared in accordance with the general method of Example 165, by alkylation of 1-(5-((3-fluorophenyl)ethynyl)pyrazin-2-yl)-4,4-dimethyltetrahydropyrimidin-2(1H)-one (Example 166) with methyl iodide.

Example 168 6,6-Dimethyl-3-(5-(phenylethynyl)pyrazin-2-yl)-1,3-oxazinan-2-one

Step 1: 2-Bromo-5-phenylethynyl-pyrazine

To a solution of 2-bromo-5-iodopyrazine (500 mg, 1.76 mmol), phenylacetylene (224 mg, 241 μL, 2.19 mmol, 1.25 equiv.), triethylamine (533 mg, 734 μL, 5.27 mmol, 3 equiv.), bis(triphenylphosphine)palladium (II) chloride (73.9 mg, 0.105 mmol, 0.06 equiv.) and triphenyl-phosphine (13.8 mg, 0.053 mmol, 0.03 equiv.) in 10 ml of THF was added under an Argon atmosphere copper (I) iodide (10.0 mg, 0.053 mmol, 0.03 equiv.). The suspension was warmed to 60° C. overnight, taken up in 5 ml of ethyl acetate and adsorbed on 4 g of silica. Purification by flash chromatography on silicagel using a 2:1 ethyl acetate/heptane mixture yielded the title compound as a light brown solid (107 mg, 23% yield). The material was directly used in the next step without further characterization.

Step 2: 2-Methyl-4-(5-phenylethynyl-pyrazin-2-ylamino)-butan-2-ol

A solution of 2-bromo-5-(phenylethynyl)pyrazine (Example 168, step 1) (158 mg, 0.061 mmol) and 4-amino-2-methylbutan-2-ol hydrochloride (255 mg, 1.83 mmol, 30 equiv.) and triethylamine (185 mg, 255 μl, 1.83 mmol, 30 equiv.) in 3 ml pyridine was stirred overnight at 85° C. The reaction mixture was concentrated in vaccuo. After workup with dichloromethane/water/brine, and drying over magnesium sulfate, the organic phases were concentrated in vacuo. The crude product was chromatographed over a prepacked 20 g silica column eluting with a 25% to 100% ethyl acetate in heptane gradient which yielded the title compound (87.5 mg, 51% yield) as an off-white solid, MS: m/e=282.2 (M+H⁺).

Step 3: 6,6-Dimethyl-3-(5-(phenylethynyl)pyrazin-2-yl)-1,3-oxazinan-2-one

A solution of 2-methyl-4-(5-(phenylethynyl)pyrazin-2-ylamino)butan-2-ol (Example 168, step 2) (84 mg, 0.30 mmol) and triethylamine (91 mg, 125 μl, 0.90 mmol, 3 equiv.) in 2 ml of THF was cooled to 0-5° C. and triphosgene (89 mg, 0.30 mmol, 1 equiv.) was added in portions. The mixture was stirred for 1 hr at 0-5° C. and for 2 hours at room temperature. The reaction mixture was quenched with saturated sodium carbonate solution followed by workup with ethyl acetate/water. The organic layers were combined, dried and concentrated. The crude product was chromatographed over a prepacked 20 g Silica column eluting with a heptane to 50% ethyl acetate in heptane gradient to yield the title compound (66.1 mg, 72% yield) as an off-white solid, MS: m/e=308.3 (M+H⁺).

Example 169 (RS)-3-[5-(3-Fluoro-phenylethynyl)-pyridin-2-yl]-5-methoxy-6,6-dimethyl-[1,3]oxazinan-2-one

Step 1: (RS)-5-Methoxy-6,6-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one

The title compound was obtained as a light brown solid, MS: m/e=333.2 (M+H⁺), using chemistry similar to that described in Example 37, step 2 from 2-bromo-5-trimethylsilanylethynyl-pyridine (Example 37, step 1) and (RS)-5-methoxy-6,6-dimethyl-[1,3]oxazinan-2-one (Example 114, step 2).

Step 2: (RS)-3-[5-(3-Fluoro-phenylethynyl)-pyridin-2-yl]-5-methoxy-6,6-dimethyl-[1,3]oxazinan-2-one

The title compound was obtained as a yellow oil, MS: m/e=355.0 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from (RS)-5-methoxy-6,6-dimethyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-[1,3]oxazinan-2-one (Example 169, step 1) and 1-fluoro-3-iodobenzene.

Example 170 (3aRS,6aSR)-1-Methyl-3-(6-phenylethynyl-pyridazin-3-yl)-hexahydro-cyclopentaimidazol-2-one

To a solution of (3aRS, 6aSR)-1-methyl-hexahydro-cyclopentaimidazol-2-one (Example 106, step 3) (55 mg, 0.39 mmol, 1.5 equiv.) in 3 ml of DMF was added 60% sodium hydride suspension in mineral oil (17 mg, 0.42 mmol, 1.6 equiv.). The white suspension was stirred for 30 min. at room temperature. Then 3-chloro-6-(phenylethynyl)pyridazine (CAS 77778-15-5) (56 mg, 0.261 mmol) was added and the reaction was stirred for 1 hour at room temperature. After workup with ethyl acetate/water, drying over magnesium sulfate and concentration in vaccuo, the residue was purified by flash chromatography over silica gel eluting with a heptane to 50% ethyl acetate/heptane gradient to yield 40 mg (48% yield) of the title compound as an off-white solid, MS: m/e=319.1 (M+H⁺).

Example 171 (RS)-6-Methyl-4-(5-phenylethynyl-pyridin-2-yl)-morpholin-3-one

Step 1: (RS)-4-(5-Iodo-pyridin-2-yl)-6-methyl-morpholin-3-one

The title compound was obtained as a white solid, MS: m/e=319.0 (M+H⁺), using chemistry similar to that described in Example 37, step 2 from 2,5-diiodopyridine and (RS)-6-methyl-morpholin-3-one (CAS 127958-63-8).

Step 2: (RS)-6-Methyl-4-(5-phenylethynyl-pyridin-2-yl)-morpholin-3-one

The title compound was obtained as a light yellow solid, MS: m/e=293.1 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from (RS)-4-(5-iodo-pyridin-2-yl)-6-methyl-morpholin-3-one (Example 171, step 1) with phenylacetylene.

Example 172 6,6-Dimethyl-4-(5-phenylethynyl-pyridin-2-yl)-morpholin-3-one

Step 1: (2-Dibenzylamino-1,1-dimethyl-ethoxy)-acetic acid ethyl ester

(4.9 g, 18.2 mmol) 1-(Dibenzylamino)-2-methylpropan-2-ol (CAS 344868-41-3) was dissolved in dichloroethane (50 ml) and ethyl 2-diazoacetate (2.83 ml, 27.3 mmol, 1.5 equiv.) and rhodium(II) acetate dimer (200 mg, 0.455 mmol, 0.025 equiv.) were added carefully at room temperature. The mixture was stirred for 3 hours at 80° C. The reaction mixture was evaporated with isolute and the crude product was purified by flash chromatography by directly loading the residue onto a silica gel column and eluting with a heptane:ethyl acetate gradient 100:0 to 70:30. The desired (2-dibenzylamino-1,1-dimethyl-ethoxy)-acetic acid ethyl ester (1.03 g, 80% purity, 13% yield) was obtained as a colorless liquid, MS: m/e=356.3 (M+H⁺).

Step 2: 6,6-Dimethyl-morpholin-3-one

(2-Dibenzylamino-1,1-dimethyl-ethoxy)-acetic acid ethyl ester (Example 172, step 1) was hydrogenated in EtOH with Pd(OH)₂ for 16 hours at 60° C. The desired 6,6-dimethyl-morpholin-3-one (585 mg, 60% purity, quant.) was obtained as a colorless liquid, MS: m/e=129 (M+H⁺) and used in the next step without further purification.

Step 3: 6,6-Dimethyl-4-(5-trimethylsilanylethynyl-pyridin-2-yl)-morpholin-3-one

The title compound was obtained as a yellow oil, MS: m/e=303.2 (M+H⁺), using chemistry similar to that described in Example 37, step 2 from 2-bromo-5-trimethylsilanylethynyl-pyridine (Example 37, step 1) and 6,6-dimethyl-morpholin-3-one (Example 172, step 2).

Step 4: 6,6-Dimethyl-4-(5-phenylethynyl-pyridin-2-yl)-morpholin-3-one

The title compound was obtained as a white solid, MS: m/e=307.3 (M+H⁺), using chemistry similar to that described in Example 37, step 3 from 6,6-dimethyl-4-(5-trimethylsilanylethynyl-pyridin-2-yl)-morpholin-3-one (Example 172, step 3) and iodobenzene.

Example 173 1,1-Dioxo-4-(5-phenylethynyl-pyridin-2-yl)-thiomorpholin-3-one

Step 1: 4-(5-Bromo-pyridin-2-yl)-thiomorpholin-3-one

The title compound was obtained as a yellow solid, MS: m/e=273.0/274.9 (M+H⁺), using chemistry similar to that described in Example 37, step 2 from 2,5-dibromopyridine and thiomorpholin-3-one.

Step 2: 4-(5-Bromo-pyridin-2-yl)-1,1-dioxo-thiomorpholin-3-one

(240 mg, 0.88 mmol) 4-(5-Bromo-pyridin-2-yl)-thiomorpholin-3-one (Example 173, step 1) was dissolved in dichloroethane (10 ml) and mCPBA (300 mg, 1.76 mmol, 2 equiv.) was added at 0-5° C. The mixture was stirred for 2 hours at 20-25° C. The reaction mixture was extracted with saturated NaHCO₃ solution and five times dichloromethane. The organic layers were combined, dried over Na₂SO₄ and evaporated to dryness. The desired 4-(5-bromo-pyridin-2-yl)-1,1-dioxo-thiomorpholin-3-one (167 mg, 62% yield) was obtained as a light brown solid, MS: m/e=305.1/307.1 (M+H⁺).

Step 3: 1,1-Dioxo-4-(5-phenylethynyl-pyridin-2-yl)-thiomorpholin-3-one

The title compound was obtained as a light brown solid, MS: m/e=327.2 (M+H⁺), using chemistry similar to that described in Example 1, step 3 from 4-(5-bromo-pyridin-2-yl)-1,1-dioxo-thiomorpholin-3-one (Example 173, step 2) and phenylacetylene.

Example 174

(3 aSR,6aRS)-1-[6-(3-Fluoro-phenylethynyl)-pyridazin-3-yl]-3-methyl-hexahydro-cyclopentaimidazol-2-one

Step 1: 3-Chloro-6-(3-fluoro-phenylethynyl)-pyridazine

To a well stirred solution of 2-chloro-5-iodopyrazine (600 mg, 2.5 mmol), 3-fluorophenyl-acetylene (315 mg, 303 μl, 2.62 mmol, 1.05 equiv.) in 7 ml of THF were added under argon atmosphere bis(triphenylphosphine)-palladium(II)dichloride (175 mg, 0.250 mmol, 0.02 equiv.), copper(I) iodide (23.8 mg, 0.125 mmol, 0.01 equiv.) and triethylamine (556 mg, 761 ul, 5.49 mmol, 2.2 equiv.). The mixture was stirred for 2 hours at room temperature. The crude mixture was filtered, adsorbed on silicagel and purified by flash chromatography over a 50 g silicagel column using a heptane to 25% ethyl acetate in heptane gradient. The title compound (450 mg, 78% yield) was obtained as a crystalline light-yellow solid, MS: m/e=233.1, 235.0 (M+H⁺).

Step 2: (3aSR,6aRS)-1-[6-(3-Fluoro-phenylethynyl)-pyridazin-3-yl]-3-methyl-hexahydro-cyclopentaimidazol-2-one

The title compound, an off-white solid, MS: m/e=337.2 (M+H⁺), was prepared in accordance with the general method of Example 170; starting from 3-chloro-6-((3-fluorophenyl)-ethynyl)pyridazine and (3aRS, 6aSR)-1-methyl-hexahydro-cyclopentaimidazol-2-one. 

1. The compound of formula I-B 1

wherein U is ═N— or ═C(R⁵)—; V is —CH═ or —N═; W is ═CH— or ═N—; with the proviso that only one of U, V or W is nitrogen. R⁵ is hydrogen, methyl or halogen; R¹ is phenyl or heteroaryl, each of which is optionally substituted by one or two substituents, selected from halogen, lower alkyl and lower alkoxy; R² and R^(2′) are each independently hydrogen, lower alkyl, hydroxy, lower alkoxy, C₃-C₆-cycloalkyl, or CH₂-lower alkoxy, or together with the carbon atom to which they are attached form a C₃-C₆-cycloalkyl group or a ring containing —CH₂OCH₂—; R³ and R^(3′) are each independently hydrogen, lower alkyl, or CH₂-lower alkoxy or together with the carbon atom to which they are attached form a C₃-C₆-cycloalkyl group; or R³ and R² together with the carbon atom to which they are attached form a C₃₋₆-cycloalkyl group or a ring containing —(CH₂)₂OCH₂—; and R⁷ and R^(7′) are each independently hydrogen, hydroxy, lower alkyl or lower alkoxy; or a pharmaceutically acceptable acid addition salt, a racemic mixture, an enantiomer, an optical isomer and/or stereoisomer thereof.
 2. The compound of claim 1, selected from the group consisting of 4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one; (3RS)-3-hydroxy-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one; 1-(3-fluoro-5-phenylethynyl-pyridin-2-yl)-4,4-dimethyl-pyrrolidin-2-one; 1-[5-(5-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-one; 4,4-dimethyl-1-(5-pyridin-3-ylethynyl-pyridin-2-yl)-pyrrolidin-2-one; 1-[5-(5-chloro-pyridin-3-ylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-one; 1-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-one; 4,4-dimethyl-1-(3-methyl-5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one; 2-(5-phenylethynyl-pyridin-2-yl)-2-aza-spiro[4.4]nonan-3-one; (RS)-3-methoxy-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one and a pharmaceutically acceptable acid addition salt, a racemic mixture, an enantiomer, an optical isomer and/or stereoisomer thereof.
 3. The compound of claim 1, selected from the group consisting of (5R or 5S)-5-methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one; (5S or 5R)-5-methoxymethyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one; (RS)-1-[5-(5-chloro-pyridin-3-ylethynyl)-pyridin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one; (RS)-3-methoxy-4,4-dimethyl-1-(5-m-tolylethynyl-pyridin-2-yl)-pyrrolidin-2-one; (RS)-1-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one; (RS)-1-[5-(4-fluoro-phenylethynyl)-pyridin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one; 6-(5-phenylethynyl-pyridin-2-yl)-2-oxa-6-aza-spiro[3.4]octan-7-one; 4,4-dimethyl-5′-phenylethynyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one; 5′-(3-fluoro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one; 5′-(3-chloro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one and a pharmaceutically acceptable acid addition salt, a racemic mixture, an enantiomer, an optical isomer and/or stereoisomer thereof.
 4. The compound of claim 1, selected from the group consisting of 5′-(5-chloro-pyridin-3-ylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one; 5′-(4-fluoro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one; 5′-(2,5-difluoro-phenylethynyl)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one; 4,4-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one; 2-(5-phenylethynyl-pyrimidin-2-yl)-2-aza-spiro[4.4]nonan-3-one; 1-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2-one; 1-[5-(3-chloro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2-one; 1-[5-(4-fluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2-one; 1-[5-(2,5-difluoro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2-one and a pharmaceutically acceptable acid addition salt, a racemic mixture, an enantiomer, an optical isomer and/or stereoisomer thereof.
 5. The compound of claim 1, selected from the group consisting of (RS)-3-methoxy-4,4-dimethyl-1-(5-phenylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one; (5R or 5S)-5-methoxymethyl-3-(5-phenylethynyl-pyrimidin-2-yl)-oxazolidin-2-one; (5S or 5R)-5-methoxymethyl-3-(5-phenylethynyl-pyrimidin-2-yl)-oxazolidin-2-one; (RS)-1-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one; (R or S)-1-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one; (S or R)-1-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one; (R or S)-1-[5-(2,5-difluoro-phenylethynyl)-pyrimidin-2-yl]-3-methoxy-4,4-dimethyl-pyrrolidin-2-one; 4,4-dimethyl-1-(6-(phenylethynyl)pyridazin-3-yl)pyrrolidin-2-one; 4,4-dimethyl-1-(5-(pyridin-3-ylethynyl)pyrazin-2-yl)pyrrolidin-2-one and a pharmaceutically acceptable acid addition salt, a racemic mixture, an enantiomer, an optical isomer and/or stereoisomer thereof.
 6. The compound of claim 4 wherein said compound is 1-[5-(3-chloro-phenylethynyl)-pyrimidin-2-yl]-4,4-dimethyl-pyrrolidin-2-one or a pharmaceutically acceptable acid addition salt, a racemic mixture, an enantiomer, an optical isomer and/or stereoisomer thereof. 